Compositions, Dosage Forms, and Co-Administration of an Opioid Agonist Compound and an Analgesic Compound

ABSTRACT

The present invention relates generally to the co-administration of an opioid agonist compound and an analgesic compound. In addition, the invention relates to, among other things, dosage forms for co-administration of an opioid agonist compound and an analgesic compound, methods for administering an opioid agonist compound and an analgesic compound, compositions comprising an opioid agonist compound and an analgesic compound, dosage forms comprising an opioid agonist compound and an analgesic compound, and so on.

This application is a continuation of U.S. patent application Ser. No.15/254,830, filed on Sep. 1, 2016, which is a continuation of U.S.patent application Ser. No. 14/356,486, filed May 6, 2014, now U.S. Pat.No. 9,457,024, which is a 35 U.S.C. § 371 application of InternationalApplication No. PCT/US2012/063725, filed Nov. 6, 2012, designating theUnited States, which claims the benefit of priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application Ser. No. 61/556,693, filedon Nov. 7, 2011, the disclosures of which are incorporated by referencein their entireties.

The present invention relates generally to the co-administration of anopioid agonist compound and an analgesic. In addition, the inventionrelates to, among other things, dosage forms for co-administration of anopioid agonist compound and an analgesic, methods for administering anopioid agonist compound and an analgesic, compositions comprising anopioid agonist compound and an analgesic, dosage forms comprising anopioid agonist compound and an analgesic, and so on.

Opioid agonists that target the mu opioid receptor are oftenadministered in combination with a second analgesic, such as anantipyretic drug and/or a non-steroidal anti-inflammatory drug (NSAID).In some cases, it is believed that such combinations result in aadditive, and in some cases, a synergistic effect when used for thetreatment of pain. Examples of FDA approved combinations includePERCOCET® (oxycodone/acetaminophen) and VICODIN®(hydrocodone/acetaminophen). Due to the improved analgesic effect, suchcombinations may be dosed in a manner that lessens the amount of opioidadministered to a patient (“opioid sparing”). Thus, the combinationsprovide a potential means for lessening the abuse potential of highlyaddictive opioids. Further, they may also lessen other side effectscaused by opioids.

Even though measures have been taken to reduce the amount of opioidsadministered to patients, the abuse of opioids has risen to epidemicproportions in the United States. FDA Consumer Health Information, FDAActs to Reduce Harm from Opioid Drugs, April 2011. The FDA estimatesthat in 2007, more than 33 million Americans misused opioids, anincrease from 29 million five years earlier. While the U.S. governmentplans to address the epidemic through education and monitoring programs,such strategies may not sufficiently address the core of the problem,which is the addictive nature of the underlying opioid compounds.

One possible means to address the underlying addictive properties ofopioids is to reduce the rate at which opioids enter the central nervoussystem. To this end, certain opioid agonist compounds have been preparedand are believed to reduce the rate of opioid entry into the centralnervous system. U.S. Patent Application Publication No. 2010/0048602,International Patent Application Publication No. WO 2008/112288,International Patent Application Publication No. WO 2010/033195, U.S.Patent Application Publication No. 2011/0237614, International PatentApplication Publication No. WO 2011/011543, U.S. Patent ApplicationPublication No. 2012/0184581, International Patent ApplicationPublication No. WO 2011/088140, and U.S. patent application Ser. No.13/521,556. As a result, it is believed that the CNS side effects,including abuse potential, may be reduced by the administration of suchopioid agonist compounds. While those compounds are believed to addresssome of the CNS side effects associate with opioids, the potential forperipheral side effects (e.g. constipation) may still exist. Thecombinations disclosed herein may be useful to address those sideeffects associated with opioids, as well as those associated with theanalgesic compounds.

As such, there exists a need to further minimize the potential sideeffect profile of opioids and opioid agonist compounds. The presentinvention addresses this and other needs in the art.

In one or more embodiments of the present invention, a composition isprovided, wherein the composition comprises an opioid agonist compoundand at least one analgesic compound.

In one or more embodiments of the present invention, a composition isprovided, wherein the composition comprises an opioid agonist compoundchosen from the formula

OPIOID-X-POLY

and pharmaceutically acceptable salts thereof; wherein OPIOID is aresidue of an opioid agonist, X is a physiological stable linker, andPOLY is a water soluble oligomer, and at least one analgesic compound.

In one or more embodiments of the present invention, a composition isprovided, wherein the composition comprises an opioid agonist compoundchosen from the formula

OPIOID-X-(CH₂CH₂O)_(n)-Y

and pharmaceutically acceptable salts thereof; wherein OPIOID is aresidue of an opioid agonist, X is a physiologically stable linker, n isan integer from 1 to 10, and Y is selected from hydrogen, an end cappinggroup, and a protecting group; and at least one analgesic compound.

In one or more embodiments of the present invention, a unit dosage formof a composition is provided, wherein the composition comprises anopioid agonist compound; and at least one analgesic compound.

In one or more embodiments of the present invention, a unit dosage formof a composition is provided, wherein the composition comprises anopioid agonist compound chosen from the formula

OPIOID-X-POLY

and pharmaceutically acceptable salts thereof; wherein OPIOID is aresidue of an opioid agonist, X is a physiologically stable linker, n isan integer from 1 to 10; and at least one analgesic compound.

In one or more embodiments of the present invention, a method oftreating pain is provided, wherein the method comprises administering acomposition, wherein the composition comprises an opioid agonistcompound and at least one analgesic compound.

In one or more embodiments of the present invention, a method oftreating pain is provided, wherein the method comprises administering acomposition, wherein the composition comprises an opioid agonistcompound chosen from the formula

OPIOID-X-POLY

and pharmaceutically acceptable salts thereof; wherein OPIOID is aresidue of an opioid agonist, X is a physiological stable linker, andPOLY is a water soluble oligomer, and at least one analgesic compound.

In one or more embodiments of the present invention, a method oftreating pain is provided, wherein the method comprises administering aunit dosage form of a composition, wherein the composition comprises anopioid agonist compound; and at least one analgesic compound.

In one or more embodiments of the present invention, a method oftreating pain is provided, wherein the method comprises administering aunit dosage form of a composition, wherein the composition comprises anopioid agonist compound chosen from the formula

OPIOID-X-POLY

and pharmaceutically acceptable salts thereof; wherein OPIOID is aresidue of an opioid agonist, X is a physiological stable linker, andPOLY is a water soluble oligomer, and at least one analgesic compound.

In one or more embodiments of the present invention, a method oftreating pain is provided, wherein the method comprises administering anopioid agonist compound and at least one analgesic compound.

In one or more embodiments of the present invention, a method oftreating pain is provided, wherein the method comprises administering anopioid agonist compound chosen from the formula

OPIOID-X-POLY

and pharmaceutically acceptable salts thereof; wherein OPIOID is aresidue of an opioid agonist, X is a physiological stable linker, andPOLY is a water soluble oligomer, and at least one analgesic compound.

These and other objects, aspects, embodiments, and features of theinvention will become more fully apparent when read in conjunction withthe detailed description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts the dose response curves for certain opioid agonistcompounds and analgesics as described in Example 7.

FIG. 2 depicts the results of the acetic acid writhing assay for acombination of certain opioid agonist compounds and analgesics asdescribed in Example 7.

In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions describedbelow.

The terms “opioid drug” and “opioid agonist” are broadly used herein torefer to an organic, inorganic, or organometallic compound typicallyhaving a molecular weight of less than about 1000 Daltons (and typicallyless than 500 Daltons) and having some degree of activity as a mu, deltaand/or kappa agonist. Opioid agonists encompass oligopeptides and otherbiomolecules having a molecular weight of less than about 1500.

The term “opioid agonist compound” as used herein, refers to an opioidagonist (or residue thereof) bound to a water soluble oligomer through alinker, including pharmaceutically acceptable salts thereof. In certainembodiments, the opioid agonist compound has the formula OPIOID-X-POLY.Further embodiments of opioid agonist compounds are disclosed herein.

The terms “spacer moiety,” “linkage” and “linker” are used hereininterchangeably to refer to an atom or a collection of atoms optionallyused to link interconnecting moieties such as a terminus of a polymersegment and an opioid drug or an electrophile or nucleophile of anopioid drug. The linker moiety may be hydrolytically stable or mayinclude a physiologically hydrolyzable or enzymatically degradablelinkage. Unless the context clearly dictates otherwise, a linker moietyoptionally exists between any two elements of an opioid agonist compound(e.g., the provided opioid agonist compounds comprising a residue of anopioid agonist and a water-soluble oligomer that can be attacheddirectly or indirectly through a linker moiety).

“Water soluble oligomer” indicates a non-peptidic oligomer that is atleast 35% (by weight) soluble, in certain embodiments greater than 70%(by weight), and in certain embodiments greater than 95% (by weight)soluble, in water at room temperature. Typically, an unfiltered aqueouspreparation of a “water-soluble” oligomer transmits at least 75%, and incertain embodiments at least 95%, of the amount of light transmitted bythe same solution after filtering. In certain embodiments thewater-soluble oligomer is at least 95% (by weight) soluble in water orcompletely soluble in water. With respect to being “non-peptidic,” anoligomer is non-peptidic when it has less than 35% (by weight) of aminoacid residues.

As described herein, the opioid agonist compounds include not only theopioid agonist compounds themselves, but also the pharmaceuticallyacceptable salts or salt forms of the opioid agonist compound as well.An opioid agonist compound as described herein can possess asufficiently acidic group, a sufficiently basic group, or bothfunctional groups, and, accordingly, react with any of a number ofinorganic bases, and inorganic and organic acids, to form a salt. Acidscommonly employed to form acid addition salts are inorganic acids suchas hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid,phosphoric acid, and the like, and organic acids such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromophenyl-sulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, and the like. Examples of such salts includethe sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, propionate,decanoate, caprylate, acrylate, formate, isobutyrate, caproate,heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate,phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,gamma-hydroxybutyrate, glycolate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,mandelate, and the like.

Base addition salts include those derived from inorganic bases, such asammonium or alkali or alkaline earth metal hydroxides, carbonates,bicarbonates, and the like. Such bases useful in preparing the salts ofthis invention thus include sodium hydroxide, potassium hydroxide,ammonium hydroxide, potassium carbonate, and the like.

The terms “monomer,” “monomeric subunit” and “monomeric unit” are usedinterchangeably herein and refer to one of the basic structural units ofa polymer or oligomer. In the case of a homo-oligomer, a singlerepeating structural unit forms the oligomer. In the case of aco-oligomer, two or more structural units are repeated—either in apattern or randomly—to form the oligomer. In certain embodimentsoligomers used in connection with the present invention arehomo-oligomers. The water-soluble oligomer typically comprises one ormore monomers serially attached to form a chain of monomers. Theoligomer can be formed from a single monomer type (i.e., ishomo-oligomeric) or two or three monomer types (i.e., is co-oligomeric).

As used herein, the structure

represents a bond, which may be selected from a single bond or a doublebond. That is the solid line represents a bond and the dashed linerepresents an optional bond. When the optional bond is absent, theresult is a single bond. When the optional bond is present, the resultis a double bond.

An “oligomer” is a molecule possessing from about 2 to about 50monomers, in certain embodiments from about 2 to about 30 monomers. Thearchitecture of an oligomer can vary. Specific oligomers for use in theinvention include those having a variety of geometries such as linear,branched, or forked, to be described in greater detail below.

“PEG” or “polyethylene glycol,” as used herein, is meant to encompassany water-soluble poly(ethylene oxide). Unless otherwise indicated, a“PEG oligomer” (also called an oligoethylene glycol) is one in whichsubstantially all (and in certain embodiments all) monomeric subunitsare ethylene oxide subunits. The oligomer may, however, contain distinctend capping moieties or functional groups, e.g., for conjugation.Typically, PEG oligomers for use in the present invention will compriseone of the two following structures: “—(CH₂CH₂O)_(n)—” or“—(CH₂CH₂O)_(n-1)CH₂CH₂—,” depending upon whether the terminal oxygen(s)has been displaced, e.g., during a synthetic transformation. For PEGoligomers, “n” varies from about 2 to 50, in certain embodiments fromabout 2 to about 30, and the terminal groups and architecture of theoverall PEG can vary. When PEG further comprises a functional group, A,for linking to, e.g., an opioid agonist, the functional group whencovalently attached to a PEG oligomer does not result in formation of(i) an oxygen-oxygen bond (—O—O—, a peroxide linkage), or (ii) anitrogen-oxygen bond (N—O, O—N).

An “end capping group” is generally a non-reactive carbon-containinggroup attached to a terminal oxygen of a PEG oligomer. Exemplary endcapping groups comprise a C₁₋₅ alkyl group, such as methyl, ethyl andbenzyl), as well as aryl, heteroaryl, cyclo, heterocyclo, and the like.In certain embodiments the capping groups have relatively low molecularweights such as methyl or ethyl. The end-capping group can also comprisea detectable label. Such labels include, without limitation,fluorescers, chemiluminescers, moieties used in enzyme labeling,colorimetric labels (e.g., dyes), metal ions, and radioactive moieties.

“Branched”, in reference to the geometry or overall structure of anoligomer, refers to an oligomer having two or more polymers representingdistinct “arms” that extend from a branch point.

“Forked” in reference to the geometry or overall structure of anoligomer, refers to an oligomer having two or more functional groups(typically through one or more atoms) extending from a branch point.

A “branch point” refers to a bifurcation point comprising one or moreatoms at which an oligomer branches or forks from a linear structureinto one or more additional arms.

The term “reactive” or “activated” refers to a functional group thatreacts readily or at a practical rate under conventional conditions oforganic synthesis. This is in contrast to those groups that either donot react or require strong catalysts or impractical reaction conditionsin order to react (i.e., a “nonreactive” or “inert” group).

“Not readily reactive,” with reference to a functional group present ona molecule in a reaction mixture, indicates that the group remainslargely intact under conditions that are effective to produce a desiredreaction in the reaction mixture.

A “protecting group” is a moiety that prevents or blocks reaction of aparticular chemically reactive functional group in a molecule undercertain reaction conditions. The protecting group will vary dependingupon the type of chemically reactive group being protected as well asthe reaction conditions to be employed and the presence of additionalreactive or protecting groups in the molecule. Functional groups whichmay be protected include, by way of example, carboxylic acid groups,amino groups, hydroxyl groups, thiol groups, carbonyl groups and thelike. Representative protecting groups for carboxylic acids includeesters (such as a p-methoxybenzyl ester), amides and hydrazides; foramino groups, carbamates (such as tert-butoxycarbonyl) and amides; forhydroxyl groups, ethers and esters; for thiol groups, thioethers andthioesters; for carbonyl groups, acetals and ketals; and the like. Suchprotecting groups are well-known to those skilled in the art and aredescribed, for example, in T. W. Greene and G. M. Wuts, ProtectingGroups in Organic Synthesis, Third Edition, Wiley, New York, 1999, andreferences cited therein.

A functional group in “protected form” refers to a functional groupbearing a protecting group. As used herein, the term “functional group”or any synonym thereof encompasses protected forms thereof.

A “physiologically cleavable” bond is a hydrolyzable bond or anenzymatically degradable linkage. A “hydrolyzable” or “degradable” bondis a relatively labile bond that reacts with water (i.e., is hydrolyzed)under ordinary physiological conditions. The tendency of a bond tohydrolyze in water under ordinary physiological conditions will dependnot only on the general type of linkage connecting two central atoms butalso on the substituents attached to these central atoms. Such bonds aregenerally recognizable by those of ordinary skill in the art.Appropriate hydrolytically unstable or weak linkages include but are notlimited to carboxylate ester, phosphate ester, anhydrides, acetals,ketals, acyloxyalkyl ether, imines, orthoesters, peptides,oligonucleotides, thioesters, and carbonates.

An “enzymatically degradable linkage” means a linkage that is subject todegradation by one or more enzymes under ordinary physiologicalconditions.

“Releasably attached,” e.g., in reference to an opioid drug releasablyattached to a water-soluble oligomer, refers to an opioid drug that iscovalently attached via a linker that includes a physiologicallycleavable or degradable (including enzymatically) linkage as disclosedherein, wherein upon degradation (e.g., by hydrolysis), the opioid drugis released. The opioid drug thus released will typically correspond tothe unmodified opioid agonist, or may be slightly altered, e.g.,possessing a short organic tag of about 8 atoms, e.g., typicallyresulting from cleavage of a part of the water-soluble oligomer linkernot immediately adjacent to the opioid agonist compound. In certainembodiments, the unmodified opioid drug is released.

A “stable” linkage or bond refers to a chemical moiety or bond,typically a covalent bond, that is substantially stable in water, thatis to say, does not undergo hydrolysis under ordinary physiologicalconditions to any appreciable extent over an extended period of time.Examples of hydrolytically stable linkages include but are not limitedto the following: carbon-carbon bonds (e.g., in aliphatic chains),ethers, amides, urethanes, amines, and the like. Generally, a stablelinkage is one that exhibits a rate of hydrolysis of less than about1-2% per day under ordinary physiological conditions. Hydrolysis ratesof representative chemical bonds can be found in most standard chemistrytextbooks.

In the context of describing the consistency of oligomers in a givencomposition, “substantially” or “essentially” means nearly totally orcompletely, for instance, 95% or greater, in certain embodiments 97% orgreater, in certain embodiments 98% or greater, in certain embodiments99% or greater, and in certain embodiments 99.9% or greater.

“Monodisperse” refers to an oligomer composition wherein substantiallyall of the oligomers in the composition have a well-defined, singlemolecular weight and defined number of monomers, as determined bychromatography or mass spectrometry. Monodisperse oligomer compositionsare in one sense pure, that is, substantially comprising moleculeshaving a single and definable number of monomers rather than severaldifferent numbers of monomers (i.e., an oligomer composition havingthree or more different oligomer sizes). In certain embodiments, amonodisperse oligomer composition possesses a MW/Mn value of 1.0005 orless, and in certain embodiments, a MW/Mn value of 1.0000. By extension,a composition comprised of monodisperse opioid agonist compounds meansthat substantially all oligomers of all opioid agonist compounds in thecomposition have a single and definable number (as a whole number) ofmonomers rather than a distribution and would possess a MW/Mn value of1.0005, and in certain embodiments, a MW/Mn value of 1.0000 if theoligomer were not attached to the residue of the opioid agonist. Acomposition comprised of monodisperse opioid agonist compounds caninclude, however, one or more additional substances such as solvents,reagents, excipients, and so forth.

“Bimodal,” in reference to an oligomer composition, refers to anoligomer composition wherein substantially all oligomers in thecomposition have one of two definable and different numbers (as wholenumbers) of monomers rather than a distribution, and whose distributionof molecular weights, when plotted as a number fraction versus molecularweight, appears as two separate identifiable peaks. In certainembodiments, for a bimodal oligomer composition as described herein,each peak is generally symmetric about its mean, although the size ofthe two peaks may differ. Ideally, the polydispersity index of each peakin the bimodal distribution, Mw/Mn, is 1.01 or less, in certainembodiments 1.001 or less, in certain embodiments 1.0005 or less, and incertain embodiments a MW/Mn value of 1.0000. By extension, a compositioncomprised of bimodal opioid agonist compounds means that substantiallyall oligomers of all opioid agonist compounds in the composition haveone of two definable and different numbers (as whole numbers) ofmonomers rather than a large distribution and would possess a MW/Mnvalue of 1.01 or less, in certain embodiments 1.001 or less, in certainembodiments 1.0005 or less, and in certain embodiments a MW/Mn value of1.0000 if the oligomer were not attached to the residue of the opioidagonist. A composition comprised of bimodal opioid agonist compounds caninclude, however, one or more additional substances such as solvents,reagents, excipients, and so forth.

A “biological membrane” is any membrane, typically made from specializedcells or tissues, that serves as a barrier to at least some foreignentities or otherwise undesirable materials. As used herein a“biological membrane” includes those membranes that are associated withphysiological protective barriers including, for example: theblood-brain barrier (BBB); the blood-cerebrospinal fluid barrier; theblood-placental barrier; the blood-milk barrier; the blood-testesbarrier; and mucosal barriers including the vaginal mucosa, urethralmucosa, anal mucosa, buccal mucosa, sublingual mucosa, rectal mucosa,and so forth. In certain contexts the term “biological membrane” doesnot include those membranes associated with the middle gastro-intestinaltract (e.g., stomach and small intestines). For example, in someinstances it may be desirable for an opioid agonist compound of theinvention to have a limited ability to cross the blood-brain barrier,yet be desirable that the same compound cross the middlegastro-intestinal tract.

A “biological membrane crossing rate,” as used herein, provides ameasure of a compound's ability to cross a biological membrane (such asthe membrane associated with the blood-brain barrier). A variety ofmethods can be used to assess transport of a molecule across any givenbiological membrane. Methods to assess the biological membrane crossingrate associated with any given biological barrier (e.g., theblood-cerebrospinal fluid barrier, the blood-placental barrier, theblood-milk barrier, the intestinal barrier, and so forth), are known inthe art, described herein and/or in the relevant literature, and/or canbe determined by one of ordinary skill in the art.

“Alkyl” refers to a hydrocarbon chain, typically ranging from about 1 to20 atoms in length. Such hydrocarbon chains are preferably but notnecessarily saturated and may be branched or straight chain. In certainembodiments the hydrocarbon chain is a straight chain. Exemplary alkylgroups include methyl, ethyl, propyl, butyl, pentyl, 2-methylbutyl,2-ethylpropyl, 3-methylpentyl, and the like. As used herein, “alkyl”includes cycloalkyl when three or more carbon atoms are referenced. Incertain embodiments, alkyl includes both a straight chain and a cyclicalkyl portion, such as cyclobutylmethyl, cyclopropylmethyl, and thelike. An “alkenyl” group is an alkyl of 2 to 20 carbon atoms with atleast one carbon-carbon double bond.

The terms “substituted alkyl” or “substituted C_(q-r) alkyl” where q andr are integers identifying the range of carbon atoms contained in thealkyl group, denotes the above alkyl groups that are substituted by one,two or three halo (e.g., F, Cl, Br, I), trifluoromethyl, hydroxy, C₁₋₇alkyl (e.g., methyl, ethyl, n-propyl, isopropyl, butyl, t-butyl, and soforth), C₁₋₇ alkoxy, C₁₋₇ acyloxy, C₃₋₇ heterocyclic, amino, phenoxy,nitro, carboxy, carboxy, acyl, cyano. The substituted alkyl groups maybe substituted once, twice or three times with the same or withdifferent substituents.

“Lower alkyl” refers to an alkyl group containing from 1 to 6 carbonatoms, and may be straight chain or branched, as exemplified by methyl,ethyl, n-butyl, i-butyl, t-butyl. “Lower alkenyl” refers to a loweralkyl group of 2 to 6 carbon atoms having at least one carbon-carbondouble bond.

“Non-interfering substituents” are those groups that, when present in amolecule, are typically non-reactive with other functional groupscontained within the molecule.

“Alkoxy” refers to an —O—R group, wherein R is alkyl or substitutedalkyl, in certain embodiments C₁-C₂₀ alkyl (e.g., methoxy, ethoxy,propyloxy, benzyl, etc.), and in certain embodiments C₁-C₇.

“Acyl” refers to a —C(O)R group, wherein R is an organic radical. Incertain embodiments R may be selected from alkyl, substituted alkyl,aryl, and substituted aryl.

“Pharmaceutically acceptable excipient” or “pharmaceutically acceptablecarrier” refers to component that can be included in the compositions ofthe invention in order to provide for a composition that has anadvantage (e.g., more suited for administration to a patient) over acomposition lacking the component and that is recognized as not causingsignificant adverse toxicological effects to a patient.

The term “aryl” means an aromatic group having up to 14 carbon atoms.Aryl groups include phenyl, naphthyl, biphenyl, phenanthrenyl,naphthacenyl, and the like. “Substituted phenyl” and “substituted aryl”denote a phenyl group and aryl group, respectively, substituted withone, two, three, four or five (e.g. 1-2, 1-3 or 1-4 substituents) chosenfrom halo (F, Cl, Br, I), hydroxy, hydroxy, cyano, nitro, alkyl (e.g.,C₁₋₆ alkyl), alkoxy (e.g., C₁₋₆ alkoxy), benzyloxy, carboxy, aryl, andso forth.

An “aromatic-containing moiety” is a collection of atoms containing atleast aryl and optionally one or more atoms. Suitablearomatic-containing moieties are described herein.

“Pharmacologically effective amount,” “physiologically effectiveamount,” and “therapeutically effective amount” are used interchangeablyherein to mean the amount of opioid agonist compound and/or analgesicpresent in a composition that is needed to provide a threshold level ofopioid agonist compound and/or analgesic in the bloodstream or in thetarget tissue. The precise amount will depend upon numerous factors,e.g., the particular active agent, the components and physicalcharacteristics of the composition, intended patient population, patientconsiderations, and the like, and can readily be determined by oneskilled in the art, based upon the information provided herein andavailable in the relevant literature.

A “difunctional” oligomer is an oligomer having two functional groupscontained therein, typically at its termini. When the functional groupsare the same, the oligomer is said to be homodifunctional. When thefunctional groups are different, the oligomer is said to beheterobifunctional.

A basic reactant or an acidic reactant described herein include neutral,charged, and any corresponding salt forms thereof.

The term “patient,” refers to a living organism suffering from or proneto a condition that can be prevented or treated by administration of acomposition as described herein, typically, but not necessarily, in theform of a composition comprising an opioid agonist compound and ananalgesic, and includes both humans and animals.

“Optional” or “optionally” means that the subsequently describedcircumstance may but need not necessarily occur, so that the descriptionincludes instances where the circumstance occurs and instances where itdoes not.

Unless the context clearly dictates otherwise, when the term “about”precedes a numerical value, the numerical value is understood to meanthe stated numerical value and also ±10% of the stated numerical value.

In certain embodiments, a composition comprising an opioid agonistcompound; and an analgesic compound is provided.

In certain embodiments, a composition comprising an opioid agonistcompound chosen from the formula

OPIOID-X-POLY

and pharmaceutically acceptable salts thereof, wherein OPIOID is aresidue of an opioid agonist, X is a physiological stable linker, andPOLY is a water soluble oligomer; and an analgesic compound, isprovided.

In certain embodiments, a composition comprising an opioid agonistcompound chosen from the formula

OPIOID-X-(CH₂CH₂O)_(n)-Y

and pharmaceutically acceptable salts thereof, wherein OPIOID is aresidue of an opioid agonist, X is a physiologically stable linker, n isan integer from 2 to 10, and Y is selected from hydrogen, an end cappinggroup, and a protecting group; and an analgesic compound, is provided.

In certain embodiments, the opioid agonist compound is chosen from thestructure

wherein:

R¹ is selected from hydrogen, acyl, and lower alkyl;

R² is selected from hydrogen and hydroxyl;

R³ is selected from hydrogen and alkyl;

R⁴ is hydrogen;

“---” represents an optional bond;

Y¹ is selected from O and S;

X is a physiologically stable linkage;

n is an integer from 2 to 10; and

Y is an end capping group; and pharmaceutically acceptable saltsthereof.

In certain embodiments, R¹ is selected from hydrogen and methyl; R³ isselected from hydrogen, methyl, and cyclobutylmethyl; R⁴ is hydrogen; Y¹is O; n is an integer from 2 to 10; and Y is lower alkyl.

In certain embodiments, Y is a capping group. In certain embodiments, Yis an alkyl group. In certain embodiments, Y is a lower alkyl group. Incertain embodiments, Y is methyl.

In certain embodiments, the opioid agonist compound is chosen from

wherein n is an integer selected from 2 to 10; and pharmaceuticallyacceptable salts thereof.

In certain embodiments, the opioid agonist compound is chosen from thestructure:

wherein n is an integer selected from 2 to 10; and pharmaceuticallyacceptable salts thereof.

In certain embodiments, n is 2. In certain embodiments, n is 3. Incertain embodiments, n is 4. In certain embodiments, n is 5. In certainembodiments, n is 6. In certain embodiments, n is 7. In certainembodiments, n is 8. In certain embodiments, n is 9. In certainembodiments, n is 10.

In certain embodiments, the opioid agonist compound has a structurechosen from

wherein:

N* is nitrogen;

Ar is selected from the group consisting of cyclohexyl, phenyl,halophenyl, methoxyphenyl, aminophenyl, pyridyl, furyl and thienyl;

Alk is selected from the group consisting of ethylene and propylene;

R_(II) is selected from the group consisting of lower alkyl, loweralkoxy, dimethylamino, cyclopropyl, 1-pyrrolidyl, morpholino;

R_(II)′ is selected from the group consisting of hydrogen, methyl andmethoxy;

R_(II)″ is hydrogen;

X is a linker (e.g., a covalent bond “-” or one or more atoms); and

POLY is a water-soluble, non-peptidic oligomer; and pharmaceuticallyacceptable salts thereof.

In certain embodiments of a compound of Formula II-Ca, R_(II) is loweralkyl. In certain embodiments of a compound of Formula II-Ca, R_(II) isethyl. In certain embodiments of a compound of Formula II-Ca, Ar isphenyl. In certain embodiments of a compound of Formula II-Ca, Alk isethylene. In certain embodiments of a compound of Formula II-Ca, R_(II)′is hydrogen. In certain embodiments of a compound of Formula II-Ca, POLYis an alkylene glycol oligomer. In certain embodiments of a compound ofFormula II-Ca, POLY is an ethylene glycol oligomer.

With respect to Formula II-Ca, it will be understood that, depending onthe conditions, one or both of the amines—but more typically, the aminemarked with an asterisk (“N*”) in Formula II-Ca—can be protonated.

In certain embodiments, the opioid agonist compound has a structurechosen from

wherein:

N* is nitrogen;

Ar is selected from the group consisting of cyclohexyl, phenyl,halophenyl, methoxyphenyl, aminophenyl, pyridyl, furyl and thienyl;

Alk is selected from the group consisting of ethylene and propylene;

R_(II) is selected from the group consisting of lower alkyl, loweralkoxy, dimethylamino, cyclopropyl, 1-pyrrolidyl, morpholino;

R_(II)′ is selected from the group consisting of hydrogen, methyl andmethoxy;

R_(II)″ is hydrogen;

X is a linker (e.g., a covalent bond “-” or one or more atoms); and

POLY is a water-soluble, non-peptidic oligomer; and pharmaceuticallyacceptable salts thereof.

In certain embodiments of a compound of Formula II-Cb, R_(I) is loweralkyl. In certain embodiments of a compound of Formula II-Cb, R_(II) isethyl. In certain embodiments of a compound of Formula II-Cb, Ar isphenyl. In certain embodiments of a compound of Formula II-Cb, Alk isethylene. In certain embodiments of a compound of Formula II-Cb, R_(II)′is hydrogen. In certain embodiments of a compound of Formula II-Cb, POLYis an alkylene glycol oligomer. In certain embodiments of a compound ofFormula II-Cb, POLY is an ethylene glycol oligomer.

With respect to Formula II-Cb, it will be understood that, depending onthe conditions, one or both of the amines—but more typically, the aminemarked with an asterisk (“N*”) in Formula II-Cb—can be protonated.

In certain embodiments, the opioid agonist compound has a structurechosen from

wherein:

N* is nitrogen;

Ar is selected from the group consisting of cyclohexyl, phenyl,halophenyl, methoxyphenyl, aminophenyl, pyridyl, furyl and thienyl;

Alk is selected from the group consisting of ethylene and propylene;

R_(II) is selected from the group consisting of lower alkyl, loweralkoxy, dimethylamino, cyclopropyl, 1-pyrrolidyl, morpholino;

R_(II)′ is selected from the group consisting of hydrogen, methyl andmethoxy;

R_(II)″ is hydrogen;

each X is independently a linker (e.g., a covalent bond “-” or one ormore atoms); and

each POLY is independently a water-soluble, non-peptidic oligomer; andpharmaceutically acceptable salts thereof.

In certain embodiments of a compound of Formula II-Cc, R_(II) is loweralkyl. In certain embodiments of a compound of Formula II-Cc, R_(II) isethyl. In certain embodiments of a compound of Formula II-Cc, Ar isphenyl. In certain embodiments of a compound of Formula II-Cc, Alk isethylene. In certain embodiments of a compound of Formula II-Cc, R_(II)′is hydrogen. In certain embodiments of a compound of Formula II-Cc, POLYis an alkylene glycol oligomer. In certain embodiments of a compound ofFormula II-Cc, POLY is an ethylene glycol oligomer.

With respect to Formula II-Cc, it will be understood that, depending onthe conditions, one or both of the amines—but more typically, the aminemarked with an asterisk (“N*”) in Formula II-Cc—can be protonated.

In certain embodiments the opioid agonist compound has a structurechosen from:

wherein “n” is an integer from 1 to 30; and pharmaceutically acceptablesalts thereof. In certain embodiments, “n” is an integer from 1 to 10.In certain embodiments, n is 2. In certain embodiments, n is 3. Incertain embodiments, n is 4. In certain embodiments, n is 5. In certainembodiments, n is 6. In certain embodiments, n is 7. In certainembodiments, n is 8. In certain embodiments, n is 9. In certainembodiments, n is 10.

In certain embodiments, the analgesic compound is a non-steroidalanti-inflammatory drug (NSAID). In certain embodiments, the analgesiccompound is an antipyretic. In certain embodiments, a single analgesiccompound is present in the composition.

In certain embodiments, the analgesic compound is selected fromketorolac, ibuprofen, oxaprozin, indomethecin, etodolac, meloxicam,sulindac, diclofenac, flufenamic acid, difunisal, naproxen,flurbiprofen, ketoprofen, fenoprofen, and acetaminophen.

In certain embodiments, the composition is in a unit dosage form.

In certain embodiments, the compositions disclosed herein are understoodto be suitable for pharmaceutical administration. In certainembodiments, the compositions are pharmaceutical compositions.

As indicated above, the present disclosure is directed to (among otherthings) a composition (or combination) comprising opioid agonistcompounds chosen from the formula:

OPIOID-X-POLY

and pharmaceutically acceptable salts thereof; wherein OPIOID is aresidue of an opioid agonist, X is a physiological stable linker, andPOLY is a water soluble oligomer, and an analgesic compound. While boththe opioid agonist compounds and analgesic are understood to alleviatepain when administered individually, the present combinations provide anadditive effect when administered for the treatment of pain. In certainembodiments, a synergistic effect may be observed when administered forthe treatment of pain. That is, the analgesic effect of the combinationis larger than the sum of the analgesic effect of each individualcomponent when administered alone.

The ability of the compositions and combinations disclosed herein totreat pain may be measured by assays known to one of skill in the art.Certain assays may include, but are not limited to, acid writhing assays(e.g. acetic acid, phenylquinone), carageenan assay, complete Freund'sadjuvant assay, formalin paw assay, and the radiant heat tail-flickassay. The compositions and combinations disclosed herein may be testedin a suitable analgesic assay. In certain embodiments, several dosagesof each opioid agonist compound and analgesic will be administeredindividually and measured using an appropriate assay for measuring ananalgesic effect. Based on the results of the individual administration,a suitable dose of each component (opioid agonist compound andanalgesic) may be tested in combination.

While it is known in the art that certain combinations of opioids andanalgesics provide an additive and possibly synergistic effect, theliterature indicates that such effects may be difficult to predict.Zelcer et al., Brain Research, 1040 (2005), pp. 151-156. Factors thatmay be relevant to the combined effect are reportedly the analgesicadministered, the opioid administered, the type of pain and/or theparticular pain model employed when measuring the effect of theadministration of such combinations.

It is believed that the combinations and compositions disclosed hereinwill have several therapeutic advantages. The combination may allow forreduced dosing and therefore reduced side effects from either of thecomponents (opioid agonist compound and analgesic compound), thusimproving the overall therapeutic window for the combination. Such acombination may also increase the suitability of thecomposition/combination for chronic use.

The compositions described herein may also comprise one or morepharmaceutical excipients. Exemplary excipients include, withoutlimitation, carbohydrates, inorganic salts, antimicrobial agents,antioxidants, surfactants, buffers, acids, bases, and combinationsthereof.

A carbohydrate such as a sugar, a derivatized sugar such as an alditol,aldonic acid, an esterified sugar, and/or a sugar polymer may be presentas an excipient. Specific carbohydrate excipients include, for example:monosaccharides, such as fructose, maltose, galactose, glucose,D-mannose, sorbose, and the like; disaccharides, such as lactose,sucrose, trehalose, cellobiose, and the like; polysaccharides, such asraffinose, melezitose, maltodextrins, dextrans, starches, and the like;and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol,sorbitol (glucitol), pyranosyl sorbitol, myoinositol, and the like.

The excipient can also include an inorganic salt or buffer such ascitric acid, sodium chloride, potassium chloride, sodium sulfate,potassium nitrate, sodium phosphate monobasic, sodium phosphate dibasic,and combinations thereof.

The preparation may also include an antimicrobial agent for preventingor deterring microbial growth. Nonlimiting examples of antimicrobialagents suitable for the present invention include benzalkonium chloride,benzethonium chloride, benzyl alcohol, cetylpyridinium chloride,chlorobutanol, phenol, phenylethyl alcohol, phenylmercuric nitrate,thimersol, and combinations thereof.

An antioxidant can be present in the preparation as well. Antioxidantsare used to prevent oxidation, thereby preventing the deterioration ofthe opioid agonist compound or other components of the preparation (e.g.analgesic). Suitable antioxidants for use in the present inventioninclude, for example, ascorbyl palmitate, butylated hydroxyanisole,butylated hydroxytoluene, hypophosphorous acid, monothioglycerol, propylgallate, sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite, and combinations thereof.

A surfactant may be present as an excipient. Exemplary surfactantsinclude: polysorbates, such as “Tween 20” and “Tween 80,” and pluronicssuch as F68 and F88 (both of which are available from BASF, Mount Olive,N.J.); sorbitan esters; lipids, such as phospholipids such as lecithinand other phosphatidylcholines, phosphatidylethanolamines (althoughpreferably not in liposomal form), fatty acids and fatty esters;steroids, such as cholesterol; and chelating agents, such as EDTA, zincand other such suitable cations.

Pharmaceutically acceptable acids or bases may be present as anexcipient in the preparation. Nonlimiting examples of acids that can beused include those acids selected from the group consisting ofhydrochloric acid, acetic acid, phosphoric acid, citric acid, malicacid, lactic acid, formic acid, trichloroacetic acid, nitric acid,perchloric acid, phosphoric acid, sulfuric acid, fumaric acid, andcombinations thereof. Examples of suitable bases include, withoutlimitation, bases selected from the group consisting of sodiumhydroxide, sodium acetate, ammonium hydroxide, potassium hydroxide,ammonium acetate, potassium acetate, sodium phosphate, potassiumphosphate, sodium citrate, sodium formate, sodium sulfate, potassiumsulfate, potassium fumerate, and combinations thereof.

The amount of the opioid agonist compound and the analgesic in thecomposition will vary depending on a number of factors, but willoptimally be a therapeutically effective dose when the composition isstored in a unit dose container. A therapeutically effective dose can bedetermined experimentally by repeated administration of increasingamounts of the active components in order to determine which amountsproduce a clinically desired endpoint. Generally, a therapeuticallyeffective amount of each component (e.g. opioid agonist compound and/oranalgesic) will range from about 0.001 mg to 1000 mg, in certainembodiments from about 0.01 mg to about 750 mg, and in certainembodiments from about 0.10 mg to about 500 mg.

The amount of any individual excipient in the composition will varydepending on the activity of the excipient and particular needs of thecomposition. Typically, the optimal amount of any individual excipientis determined through routine experimentation, i.e., by preparingcompositions containing varying amounts of the excipient (ranging fromlow to high), examining the stability and other parameters, and thendetermining the range at which optimal performance is attained with nosignificant adverse effects.

Generally, however, the excipient will be present in the composition inan amount of about 1% to about 99% by weight, in certain embodimentsfrom about 5%-98% by weight, in certain embodimentsfrom about 15-95% byweight of the excipient, and in certain embodiments concentrations lessthan 30% by weight.

These foregoing pharmaceutical excipients along with other excipientsand general teachings regarding pharmaceutical compositions aredescribed in “Remington: The Science & Practice of Pharmacy”, 19th ed.,Williams & Williams, (1995), the “Physician's Desk Reference”, 52^(nd)ed. Medical Economics, Montvale, N.J. (1998), and Kibbe, A. H., Handbookof Pharmaceutical Excipients, 3^(rd) Edition, American PharmaceuticalAssociation, Washington, D.C., 2000.

The pharmaceutical compositions can take any number of forms and theinvention is not limited in this regard. In certain embodiments,preparations are in a form suitable for oral administration such as atablet, caplet, capsule, gel cap, troche, dispersion, suspension,solution, elixir, syrup, lozenge, but can be in other forms as well,such as transdermal patch, spray, suppository, and powder.

Oral dosage forms are preferred and include tablets, caplets, capsules,gel caps, suspensions, solutions, elixirs, and syrups, and can alsocomprise a plurality of granules, beads, powders or pellets that areoptionally encapsulated. Such dosage forms are prepared usingconventional methods known to those in the field of pharmaceuticalformulation and described in the pertinent texts.

Tablets and caplets, for example, can be manufactured using standardtablet processing procedures and equipment. Direct compression andgranulation techniques are preferred when preparing tablets or capletscontaining the compositions described herein. In addition to the activecomponents, the tablets and caplets will generally contain inactive,pharmaceutically acceptable carrier materials such as binders,lubricants, disintegrants, fillers, stabilizers, surfactants, coloringagents, and the like. Binders are used to impart cohesive qualities to atablet, and thus ensure that the tablet remains intact. Suitable bindermaterials include, but are not limited to, starch (including corn starchand pregelatinized starch), gelatin, sugars (including sucrose, glucose,dextrose and lactose), polyethylene glycol, waxes, and natural andsynthetic gums, e.g., acacia sodium alginate, polyvinylpyrrolidone,cellulosic polymers (including hydroxypropyl cellulose, hydroxypropylmethylcellulose, methyl cellulose, microcrystalline cellulose, ethylcellulose, hydroxyethyl cellulose, and the like), and Veegum. Lubricantsare used to facilitate tablet manufacture, promoting powder flow andpreventing particle capping (i.e., particle breakage) when pressure isrelieved. Useful lubricants are magnesium stearate, calcium stearate,and stearic acid. Disintegrants are used to facilitate disintegration ofthe tablet, and are generally starches, clays, celluloses, algins, gums,or crosslinked polymers. Fillers include, for example, materials such assilicon dioxide, titanium dioxide, alumina, talc, kaolin, powderedcellulose, and microcrystalline cellulose, as well as soluble materialssuch as mannitol, urea, sucrose, lactose, dextrose, sodium chloride, andsorbitol. Stabilizers, as well known in the art, are used to inhibit orretard drug decomposition reactions that include, by way of example,oxidative reactions.

In certain embodiments, the oral dosage form is a capsule, in which thecomposition can be encapsulated in the form of a liquid or gel (e.g., inthe case of a gel cap) or solid (including particulates such asgranules, beads, powders or pellets). Suitable capsules include hard andsoft capsules, and are generally made of gelatin, starch, or acellulosic material. Two-piece hard gelatin capsules are preferablysealed, such as with gelatin bands or the like.

Included are parenteral formulations in the substantially dry form(typically as a lyophilizate or precipitate, which can be in the form ofa powder or cake), as well as formulations prepared for injection, whichare typically liquid and requires the step of reconstituting the dryform of parenteral formulation. Examples of suitable diluents forreconstituting solid compositions prior to injection includebacteriostatic water for injection, dextrose 5% in water,phosphate-buffered saline, Ringer's solution, saline, sterile water,deionized water, and combinations thereof.

In some cases, compositions intended for parenteral administration cantake the form of nonaqueous solutions, suspensions, or emulsions, eachtypically being sterile. Examples of nonaqueous solvents or vehicles arepropylene glycol, polyethylene glycol, vegetable oils, such as olive oiland corn oil, gelatin, and injectable organic esters such as ethyloleate.

The parenteral formulations described herein can also contain adjuvantssuch as preserving, wetting, emulsifying, and dispersing agents. Theformulations are rendered sterile by incorporation of a sterilizingagent, filtration through a bacteria-retaining filter, irradiation, orheat.

The composition can also be administered through the skin usingconventional transdermal patch or other transdermal delivery system,wherein the composition is contained within a laminated structure thatserves as a drug delivery device to be affixed to the skin. In such astructure, the opioid agonist compound and/or analgesic is contained ina layer, or “reservoir,” underlying an upper backing layer. Thelaminated structure can contain a single reservoir, or it can containmultiple reservoirs.

The composition can also be formulated into a suppository for rectaladministration. With respect to suppositories, the opioid agonistcompound and analgesic are mixed with a suppository base material whichis (e.g., an excipient that remains solid at room temperature butsoftens, melts or dissolves at body temperature) such as cocoa butter(theobroma oil), polyethylene glycols, glycerinated gelatin, fattyacids, and combinations thereof. Suppositories can be prepared by, forexample, performing the following steps (not necessarily in the orderpresented): melting the suppository base material to form a melt;incorporating the opioid agonist compound and/or analgesic (eitherbefore or after melting of the suppository base material); pouring themelt into a mold; cooling the melt (e.g., placing the melt-containingmold in a room temperature environment) to thereby form suppositories;and removing the suppositories from the mold.

The invention also provides a method for administering the compositionas provided herein to a patient suffering from a condition that isresponsive to treatment with the opioid agonist compound and/oranalgesic, such as pain. The method comprises administering, generallyorally, a therapeutically effective amount of the composition. Themethod specifically includes compositions comprising combinations of anyof the opioid agonist compounds disclosed herein and any of theanalgesic compounds disclosed herein. Other modes of administration arealso contemplated, such as pulmonary, nasal, buccal, rectal, sublingual,transdermal, and parenteral. As used herein, the term “parenteral”includes subcutaneous, intravenous, intra-arterial, intraperitoneal,intracardiac, intrathecal, and intramuscular injection, as well asinfusion injections.

The invention also provides a method for administering an opioid agonistcompound and at least one analgesic compound, as provided herein, to apatient suffering from a condition that is responsive to treatment withthe opioid agonist compound and/or analgesic, such as pain. The methodspecifically includes combinations of any of the opioid agonistcompounds disclosed herein and any of the analgesic compounds disclosedherein. In such a method, in certain embodiments, the opioid agonistcompound and at least one analgesic compound are not administered aspart of the same composition. The method comprises administering,generally orally, a therapeutically effective amount of an opioidagonist compound and at least one analgesic compound. Each may bepresent in a separate composition, and in certain embodiments, eachseparate composition is present in a separate unit dosage form. Othermodes of administration are also contemplated, such as pulmonary, nasal,buccal, rectal, sublingual, transdermal, and parenteral. As used herein,the term “parenteral” includes subcutaneous, intravenous,intra-arterial, intraperitoneal, intracardiac, intrathecal, andintramuscular injection, as well as infusion injections.

In instances where parenteral administration is utilized, it may benecessary to employ somewhat bigger oligomers than those describedpreviously (e.g., polymers), with molecular weights ranging from about500 to 30 kilodaltons (e.g., having molecular weights of about 500daltons, 1000 daltons, 2000 daltons, 2500 daltons, 3000 daltons, 5000daltons, 7500 daltons, 10000 daltons, 15000 daltons, 20000 daltons,25000 daltons, 30000 daltons or even more).

The methods of administering may be used to treat any condition that canbe remedied or prevented by administration of the particular opioidagonist compound and analgesic. Most commonly, the compositions andcombinations provided herein are administered for the management ofchronic pain. As such, the methods disclosed herein include methods fortreating pain, for example, by administering the compositions andcombinations provided herein. Those of ordinary skill in the artappreciate which conditions a specific opioid agonist compound andanalgesic can effectively treat. The actual dose to be administered willvary depend upon the age, weight, and general condition of the subjectas well as the severity of the condition being treated, the judgment ofthe health care professional, opioid agonist compound, and analgesicbeing administered. Therapeutically effective amounts are known to thoseskilled in the art and/or are described in the pertinent reference textsand literature. Generally, a therapeutically effective amount of eachcomponent (e.g. opioid agonist compound and/or analgesic) will rangefrom about 0.001 mg to 1000 mg, in certain embodiments in doses from0.01 mg to 750 mg, and in certain embodiments in doses from 0.10 mg to500 mg.

In certain embodiments, the composition will be in a unit dosage form tothereby provide a unit dosage suitable for single administration of adosage of each active component in the unit dosage form. Suitablepharmaceutical compositions and dosage forms may be prepared usingconventional methods known to those in the field of pharmaceuticalformulation and described in the pertinent texts and literature, e.g.,in Remington's Pharmaceutical Sciences: 18^(th) Edition, Gennaro, A. R.,Ed. (Mack Publishing Company; Easton, Penn.; 1990).

The unit dosage of the composition can be administered in a variety ofdosing schedules depending on the judgment of the clinician, needs ofthe patient, and so forth. The specific dosing schedule will be known bythose of ordinary skill in the art or can be determined experimentallyusing routine methods. Exemplary dosing schedules include, withoutlimitation, administration five times a day, four times a day, threetimes a day, twice daily, once daily, three times weekly, twice weekly,once weekly, twice monthly, once monthly, and any combination thereof.Once the clinical endpoint has been achieved, dosing of the compositionis halted.

Based on the covalent modification of opioid agonist molecules, theopioid agonist compounds present in the disclosed compositions andcombinations represent an improvement over the opioid agonistformulations of the prior art. That is to say, opioid agonist compoundscontaining small water-oligomers possess altered pharmacokineticprofiles, but are not subject to the risk of physical tampering thatallows for the recovery and abuse of the rapid acting opioid agonistsassociated with certain alternative delivery formulations such astransdermal patches. U.S. Patent Application Publication No.2010/0048602, International Patent Application Publication No. WO2008/112288, International Patent Application Publication No. WO2010/033195, U.S. Patent Application Publication No. 2011/0237614,International Patent Application Publication No. WO 2011/011543, U.S.Patent Application Publication No. 2012/0184581, International PatentApplication Publication No. WO 2011/088140, and U.S. patent applicationSer. No. 13/521,556. The opioid agonist compounds themselves may beuseful for eliminating the euphoric high associated with administrationof opioids while still maintaining an analgesic effect comparable tothat of unmodified opioid. The opioid agonist compounds are also usefulin reducing or eliminating CNS-side effects associated with opioid use,as well as in reducing the associated addiction and/or abuse potentialassociated therewith. As such, these and other beneficial propertieswill also be present in the compositions and combinations of the presentinvention.

Accordingly, OPIOID can be any opioid agonist, including any compoundinteracting with mu (μ), kappa (κ), or delta (δ) opioid receptors, orany combination thereof. In certain embodiments, the opioid is selectivefor the mu (μ) opioid receptor. In certain embodiments, the opioid isselective for the kappa (κ) opioid receptor. In certain embodiments, theopioid is selective for the delta (δ) opioid receptor. Opioids suitablefor use can be naturally occurring, semi-synthetic or syntheticmolecules.

In certain embodiments, OPIOID may be a residue of an opioid agonist ofthe formula:

wherein:

R¹ is selected from hydrogen, acyl, and lower alkyl;

R² is selected from hydrogen and hydroxyl;

R³ is selected from hydrogen and alkyl;

R⁴ is hydrogen;

“---” represents an optional bond;

Y¹ is selected from O and S; and

R⁵ is selected from the group consisting of

(without regard to stereochemistry), wherein R⁶ is an organic radical[including C(O)CH₃]. Exemplary R³ groups include lower alkyl such asmethyl, ethyl, isopropyl, and the like, as well as the following:

In certain embodiments, OPIOID may be a residue of an opioid agonist ofthe formula:

wherein:

N* is nitrogen;

Ar is selected from cyclohexyl, phenyl, halophenyl, methoxyphenyl,aminophenyl, pyridyl, furyl and thienyl;

Alk is selected from ethylene and propylene;

R_(II) is selected from lower alkyl, lower alkoxy, dimethylamino,cyclopropyl, 1-pyrrolidyl, morpholino

R_(II)′ is selected from hydrogen, methyl and methoxy; and

R_(II)″ is selected from hydrogen and an organic radical.

With respect to Formula II, it will be understood that, depending on theconditions, one or both of the amines—but more typically, the aminemarked with an asterisk (“N*”) in Formula II—can be protonated.

In certain embodiments R_(II) is selected from lower alkyl. In certainembodiments R_(II) is ethyl.

Opioids that may be used include, but are not limited to, acetorphine,acetyldihydrocodeine, acetyldihydrocodeinone, acetylmorphinone,alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine,bezitramide, biphalin, buprenorphine, butorphanol, clonitazene, codeine,desomorphine, dextromoramide, dezocine, diampromide, diamorphone,dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,dimethylthiambutene, dioxaphetyl butyrate, dipipanone, dynorphins(including dynorphin A and dynorphin B), endorphins (includingbeta-endorphin and α/β-neo-endorphin), enkephalins (includingMet-enkephalin and Leu-enkephalin), eptazocine, ethoheptazine,ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,dihydroetorphine, fentanyl and derivatives, heroin, hydrocodone,hydromorphone, hydroxypethidine, isomethadone, ketobemidone,levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,metazocine, methadone, metopon, morphine, myrophine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphine,normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum,pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine,piminodine, piritramide, propheptazine, promedol, properidine,propoxyphene, sufentanil, tilidine, and tramadol.

In certain embodiments, the opioid agonist is selected from hydrocodone,morphine, hydromorphone, oxycodone, codeine, levorphanol, meperidine,methadone, oxymorphone, buprenorphine, fentanyl, dipipanone, heroin,tramadol, nalbuphine, etorphine, dihydroetorphine, butorphanol, andlevorphanol.

In other embodiments, the opioid agonist is selected from fentanyl,hydromorphone, nalbuphine, morphine, codeine, oxycodone, andoxymorphone.

Any other opioid compound having opioid agonist activity may also beused. Assays for determining whether a given compound (regardless ofwhether the compound is an opioid agonist compound disclosed herein orin the parent form) can act as an agonist on an opioid receptor aredescribed herein and are known in the art.

In some instances, opioid agonists can be obtained from commercialsources. In addition, opioid agonists can be synthesized using standardtechniques of synthetic organic chemistry. Synthetic approaches forpreparing opioid agonists are described in the literature and in, forexample, U.S. Pat. Nos.: 2,628,962, 2,654,756, 2,649,454, and 2,806,033.

Each of these (and other) opioid agonists (or residues thereof) can becovalently attached (either directly or through one or more atoms) to awater-soluble oligomer. Methods for preparing such opioid agonistcompounds are disclosed in U.S. Patent Application Publication No.2010/0048602, International Patent Application Publication No. WO2008/112288, International Patent Application Publication No. WO2010/033195, U.S. Patent Application Publication No. 2011/0237614,International Patent Application Publication No. WO 2011/011543, U.S.Patent Application Publication No. 2012/0184581, International PatentApplication Publication No. WO 2011/088140, and U.S. patent applicationSer. No. 13/521,556. each of which are incorporated by reference.Specific and exemplary synthetic methods are recited in Examples 1-6below.

Opioid agonists useful in the invention generally have a molecularweight of less than about 1500 Da (Daltons), and in certain embodimentsless than about 1000 Da. Exemplary molecular weights of opioid agonistsinclude molecular weights of: less than about 950 Da; less than about900 Da; less than about 850 Da; less than about 800 Da; less than about750 Da; less than about 700 Da; less than about 650 Da; less than about600 Da; less than about 550 Da; less than about 500 Da; less than about450 Da; less than about 400 Da; less than about 350 Da; and less thanabout 300 Da.

The opioid agonists used in the invention, if chiral, may be in aracemic mixture, or an optically active form, for example, a singleoptically active enantiomer, or any combination or ratio of enantiomers(i.e., scalemic mixture). In addition, the opioid agonist may possessone or more geometric isomers. With respect to geometric isomers, acomposition can comprise a single geometric isomer or a mixture of twoor more geometric isomers. An opioid agonist for use in the presentinvention can be in its customary active form, or may possess somedegree of modification. For example, an opioid agonist may have atargeting agent, tag, or transporter attached thereto, prior to or aftercovalent attachment of a water-soluble oligomer. Alternatively, theopioid may possess a lipophilic moiety attached thereto, such as aphospholipid (e.g., distearoylphosphatidylethanolamine or “DSPE,”dipalmitoylphosphatidylethanolamine or “DPPE,” and so forth) or a smallfatty acid. In certain embodiments, however, the opioid does not includeattachment to a lipophilic moiety.

The opioid agonist for coupling to a water-soluble oligomer possesses afree hydroxyl, carboxyl, carbonyl, thio, amino group, or the like (i.e.,“handle”) suitable for covalent attachment to the oligomer. In addition,the opioid agonist can be modified by introduction of a reactive group,for example, by conversion of one of its existing functional groups to afunctional group suitable for formation of a stable covalent linkagebetween the oligomer and the opioid agonist.

Accordingly, each oligomer is composed of up to three different monomertypes selected from the group consisting of: alkylene oxide, such asethylene oxide or propylene oxide; olefinic alcohol, such as vinylalcohol, 1-propenol or 2-propenol; vinyl pyrrolidone; hydroxyalkylmethacrylamide or hydroxyalkyl methacrylate, where in certainembodiments, alkyl is methyl; a-hydroxy acid, such as lactic acid orglycolic acid; phosphazene, oxazoline, amino acids, carbohydrates suchas monosaccharides, saccharide or mannitol; and N-acryloylmorpholine. Incertain embodiments, monomer types include alkylene oxide, olefinicalcohol, hydroxyalkyl methacrylamide or methacrylate,N-acryloylmorpholine, and a-hydroxy acid. In certain embodiments, eacholigomer is, independently, a co-oligomer of two monomer types selectedfrom this group, or, in certain embodiments, is a homo-oligomer of onemonomer type selected from this group.

The two monomer types in a co-oligomer may be of the same monomer type,for example, two alkylene oxides, such as ethylene oxide and propyleneoxide. In certain embodiments, the oligomer is a homo-oligomer ofethylene oxide. Usually, although not necessarily, the terminus (ortermini) of the oligomer that is not covalently attached to an opioidagonist is capped to render it unreactive. Alternatively, the terminusmay include a reactive group. When the terminus is a reactive group, thereactive group is either selected such that it is unreactive under theconditions of formation of the final oligomer or during covalentattachment of the oligomer to an opioid agonist, or it is protected asnecessary. One common end-functional group is hydroxyl or —OH,particularly for oligoethylene oxides.

The water-soluble oligomer (e.g., “POLY” in the structures providedherein) can have any of a number of different geometries. For example,it can be linear, branched, or forked. Most typically, the water-solubleoligomer is linear or is branched, for example, having one branch point.Although much of the discussion herein is focused upon poly(ethyleneoxide) as an illustrative oligomer, the discussion and structurespresented herein can be readily extended to encompass any of thewater-soluble oligomers described above.

The molecular weight of the water-soluble oligomer, excluding the linkerportion, in certain embodiments is generally relatively low. Forexample, the molecular weight of the water-soluble oligomer is typicallybelow about 2200 Daltons, and more typically at around 1500 Daltons orbelow. In certain other embodiments, the molecular weight of thewater-soluble oligomer may be below 800 Daltons.

In certain embodiments, exemplary values of the molecular weight of thewater-soluble oligomer include less than or equal to about 500 Daltons,or less than or equal to about 420 Daltons, or less than or equal toabout 370 Daltons, or less than or equal to about 370 Daltons, or lessthan or equal to about 325 Daltons, less than or equal to about 280Daltons, less than or equal to about 235 Daltons, or less than or equalto about 200 Daltons, less than or equal to about 175 Daltons, or lessthan or equal to about 150 Daltons, or less than or equal to about 135Daltons, less than or equal to about 90 Daltons, or less than or equalto about 60 Daltons, or even less than or equal to about 45 Daltons.

In certain embodiments, exemplary values of the molecular weight of thewater-soluble oligomer, excluding the linker portion, include: belowabout 1500 Daltons; below about 1450 Daltons; below about 1400 Daltons;below about 1350 Daltons; below about 1300 Daltons; below about 1250Daltons; below about 1200 Daltons; below about 1150 Daltons; below about1100 Daltons; below about 1050 Daltons; below about 1000 Daltons; belowabout 950 Daltons; below about 900 Daltons; below about 850 Daltons;below about 800 Daltons; below about 750 Daltons; below about 700Daltons; below about 650 Daltons; below about 600 Daltons; below about550 Daltons; below about 500 Daltons; below about 450 Daltons; belowabout 400 Daltons; and below about 350 Daltons; but in each case aboveabout 250 Daltons.

In certain embodiments, rather than being bound to an oligomer, theopioid agonist is covalently attached to a water-soluble polymer, i.e.,a moiety having a more than 50 repeating subunits. For instance, themolecular weight of the water-soluble polymer, excluding the linkerportion, may be below about 80,000 Daltons; below about 70,000 Daltons;below about 60,000 Daltons; below about 50,000 Daltons; below about40,000 Daltons; below about 30,000 Daltons; below about 20,000 Daltons;below about 10,000 Daltons; below about 8,000 Daltons; below about 6,000Daltons; below about 4,000 Daltons; below about 3,000 Daltons; and belowabout 2,000 Daltons; but in each case above about 250 Daltons.

In certain embodiments, exemplary ranges of molecular weights of thewater-soluble, oligomer (excluding the linker) include: from about 45 toabout 225 Daltons; from about 45 to about 175 Daltons; from about 45 toabout 135 Daltons; from about 45 to about 90 Daltons; from about 90 toabout 225 Daltons; from about 90 to about 175 Daltons; from about 90 toabout 135 Daltons; from about 135 to about 225 Daltons; from about 135to about 175 Daltons; and from about 175 to about 225 Daltons.

In other alternative embodiments, exemplary ranges of molecular weightsof the water-soluble oligomer (excluding the linker) include: from about250 to about 1500 Daltons; from about 250 to about 1200 Daltons; fromabout 250 to about 800 Daltons; from about 250 to about 500 Daltons;from about 250 to about 400 Daltons; from about 250 to about 500Daltons; from about 250 to about 1000 Daltons; and from about 250 toabout 500 Daltons.

In other embodiments related to water-soluble polymer bound opioidagonists, exemplary ranges of molecular weights of the water-solublepolymer (excluding the linker) include: from about 2,000 to about 80,000Daltons; from about 2,000 to about 70,000 Daltons; from about 2,000 toabout 60,000 Daltons; from about 2,000 to about 50,000 Daltons; fromabout 2,000 to about 40,000 Daltons; from about 2,000 to about 30,000Daltons; from about 2,000 to about 20,000 Daltons; from about 2,000 toabout 10,000 Daltons; from about 2,000 to about 8,000 Daltons; fromabout 2,000 to about 6,000 Daltons; from about 2,000 to about 4,000Daltons; from about 2,000 to about 3,000 Daltons; from about 10,000 toabout 80,000 Daltons; from about 10,000 to about 60,000 Daltons; fromabout 10,000 to about 40,000 Daltons; from about 30,000 to about 80,000Daltons; from about 30,000 to about 60,000 Daltons; from about 40,000 toabout 80,000 Daltons; and from about 60,000 to about 80,000 Daltons.

The number of monomers in the water-soluble oligomer may be betweenabout 1 and about 1825 (inclusive), including all integer values withinthis range.

In certain embodiments, the number of monomers in the water-solubleoligomer falls within one or more of the following inclusive ranges:between 1 and 5 (i.e., is selected from 1, 2, 3, 4, and 5); between 1and 4 (i.e., can be 1, 2, 3, or 4); between 1 and 3 (i.e., selected from1, 2, or 3); between 1 and 2 (i.e., can be 1 or 2); between 2 and 5(i.e., can be selected from 2, 3, 4, and 5); between 2 and 4 (i.e., isselected from 2, 3, and 4); between 2 and 3 (i.e., is either 2 or 3);between 3 and 5 (i.e., is either 3, 4 or 5); between 3 and 4 (i.e., is 3or 4); and between 4 and 5 (i.e., is 4 or 5). In a specific instance,the number of monomers in series in the oligomer (and the correspondingopioid agonist compound) is selected from 1, 2, 3, 4, or 5. Thus, forexample, when the water-soluble oligomer includes CH₃—(OCH₂CH₂)_(n)—,“n” is an integer that can be 1, 2, 3, 4, or 5.

In certain embodiments, the number of monomers in the water-solubleoligomer falls within one or more of the following inclusive ranges:between 6 and 30 (i.e., is selected from 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, and 30);between 6 and 25 (i.e., is selected from 6, 7, 8, 9, 10, 11, 12, 13, 14,15, 16, 17, 18, 19, 20, 21, 22, 23, 24, and 25); between 6 and 20 (i.e.,is selected from 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and20); between 6 and 15 (is selected from 6, 7, 8, 9, 10, 11, 12, 13, 14,15); between 6 and 10 (i.e., is selected from 6, 7, 8, 9, and 10);between 10 and 25 (i.e., is selected from 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, and 25); and between 15 and 20 (i.e., isselected from 15, 16, 17, 18, 19, and 20). In certain instances, thenumber of monomers in series in the oligomer (and the correspondingopioid agonist compound) is one of 6, 7, 8, 9, 10, 11, 12, 13, 14, 15,16, 17, 18, 19, 20, 21, 22, 23, 24, or 25. Thus, for example, when thewater-soluble oligomer includes CH₃—(OCH₂CH₂)_(n)—, “n” is an integerthat can be 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,22, 23, 24, or 25.

In yet another embodiment, the number of monomers in the water-solubleoligomer falls within the following inclusive range: between 1 and 10,i.e., is selected from 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10.

In certain other embodiments, the number of monomers in thewater-soluble oligomer falls within one or more of the followinginclusive ranges: between 35 and 1825; between 100 and 1800; between 200and 1600; between 400 and 1400; between 600 and 1200; between 800 and1000; between 35 and 1000; between 35 and 600; between 35 and 400;between 35 and 200; between 35 and 100; between 1000 and 1825; between1200 and 1825; between 1400 and 1825; and between 1600 and 1825.

When the water-soluble oligomer has 1, 2, 3, 4, or 5 monomers, thesevalues correspond to a methoxy end-capped oligo(ethylene oxide) having amolecular weight of about 75, 119, 163, 207, and 251 Daltons,respectively. When the oligomer has 6, 7, 8, 9, 10, 11, 12, 13, 14, or15 monomers, these values correspond to a methoxy end-cappedoligo(ethylene oxide) having a molecular weight of about 295, 339, 383,427, 471, 515, 559, 603, 647, and 691 Daltons, respectively.

When the water-soluble oligomer is attached to the opioid agonist (incontrast to the step-wise addition of one or more monomers toeffectively “grow” the oligomer onto the opioid agonist), thecomposition containing an activated form of the water-soluble oligomermay be monodispersed. In those instances, however, where a bimodalcomposition is employed, the composition will possess a bimodaldistribution centering around any two of the above numbers of monomers.Ideally, the polydispersity index of each peak in the bimodaldistribution, Mw/Mn, is 1.01 or less, and in certain embodiments, is1.001 or less, and in certain embodiments is 1.0005 or less. In certainembodiments, each peak possesses a MW/Mn value of 1.0000. For instance,a bimodal oligomer may have any one of the following exemplarycombinations of monomer subunits: 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8,1-9, 1-10, and so forth; 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, and soforth; 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, and so forth; 4-5, 4-6, 4-7,4-8, 4-9, 4-10, and so forth; 5-6, 5-7, 5-8, 5-9, 5-10, and so forth;6-7, 6-8, 6-9, 6-10, and so forth; 7-8, 7-9, 7-10, and so forth; and8-9, 8-10, and so forth.

In some instances, the composition containing an activated form of thewater-soluble oligomer will be trimodal or even tetramodal, possessing arange of monomers units as previously described. Oligomer compositionspossessing a well-defined mixture of oligomers (i.e., being bimodal,trimodal, tetramodal, and so forth) can be prepared by mixing purifiedmonodisperse oligomers to obtain a desired profile of oligomers (amixture of two oligomers differing only in the number of monomers isbimodal; a mixture of three oligomers differing only in the number ofmonomers is trimodal; a mixture of four oligomers differing only in thenumber of monomers is tetramodal), or alternatively, can be obtainedfrom column chromatography of a polydisperse oligomer by recovering the“center cut”, to obtain a mixture of oligomers in a desired and definedmolecular weight range.

In certain embodiments the water-soluble oligomer is obtained from acomposition that is unimolecular or monodisperse. That is, the oligomersin the composition possess the same discrete molecular weight valuerather than a distribution of molecular weights. Some monodisperseoligomers can be purchased from commercial sources such as thoseavailable from Sigma-Aldrich, or alternatively, can be prepared directlyfrom commercially available starting materials such as Sigma-Aldrich.Water-soluble oligomers can be prepared as described in Chen and Baker,J. Org. Chem. 6870-6873 (1999), WO 02/098949, and U.S. PatentApplication Publication 2005/0136031.

When present, the spacer moiety (through which the water-solubleoligomer is attached to the opioid agonist) may be a single bond, asingle atom, such as an oxygen atom or a sulfur atom, two atoms, or anumber of atoms. In particular, “X” may represent a covalent bondbetween OPIOID and POLY, or alternatively it may represent a chemicalmoiety not present on OPIOID and/or POLY alone. A spacer moiety istypically but is not necessarily linear in nature. In certainembodiments, the spacer moiety, “X” is hydrolytically stable, and is incertain embodiments also enzymatically stable. In certain embodiments,the spacer moiety, “X” is physiologically cleavable, i.e. hydrolyticallycleavable or enzymatically degradable. In certain embodiments, thespacer moiety “X” is one having a chain length of less than about 12atoms, and in certain embodiments less than about 10 atoms, in certainembodiments less than about 8 atoms and in certain embodiments less thanabout 5 atoms, whereby length is meant the number of atoms in a singlechain, not counting substituents. For instance, a urea linkage such asthis, R_(oligomer)-NH—(C═O)—NH—R′_(OP), is considered to have a chainlength of 3 atoms (—NH—C(O)—NH—). In certain embodiments, the spacermoiety linkage does not comprise further spacer groups.

In some instances, the spacer moiety “X” comprises an ether, amide,urethane, amine, thioether, urea, or a carbon-carbon bond. Functionalgroups are typically used for forming the linkages. The spacer moietymay also comprise (or be adjacent to or flanked by) spacer groups, asdescribed further below.

More specifically, in certain embodiments, a spacer moiety, X, may beany of the following: “-” (i.e., a covalent bond, that may be stable ordegradable, between the residue of the opioid agonist and thewater-soluble oligomer), —O—, —NH—, —S—, —C(O)—, —C(O)O—, —OC(O)—,—CH₂—C(O)O—, —CH₂—OC(O)—, —C(O)O—CH₂—, —OC(O)—CH₂—, C(O)—NH, NH—C(O)—NH,O—C(O)—NH, —C(S)—, —CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—,—O—CH₂—, —CH₂—O—, —O—CH₂—CH₂—, —CH₂—O—CH₂—, —CH₂—CH₂—O—,—O—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—O—,—O—CH₂—CH₂—CH₂—CH₂—, —CH₂—O—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂—,—CH₂—CH₂—CH₂—O—CH₂—, —CH₂—CH₂—CH₂—CH₂—O—, —C(O) —NH—CH₂—,—C(O)—NH—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—, —CH₂—CH₂—C(O)—NH—, —C(O)—NH—CH₂—CH₂—CH₂—, —CH₂—C(O)—NH—CH₂—CH₂—, —CH₂—CH₂—C(O)—NH—CH₂—,—CH₂—CH₂—CH₂—C(O)—NH—, —C(O)—NH—CH₂—CH₂—CH₂—CH₂—,—CH₂—C(O)—NH—CH₂—CH₂—CH₂—, —CH₂—CH₂—C(O)—NH—CH₂—CH₂—,—CH₂—CH₂—CH₂—C(O)—NH—CH₂—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—C(O)—NH—, —NH—C(O)—CH₂—, —CH₂—NH—C(O)—CH₂—,—CH₂—CH₂—NH—C(O)—CH₂—, —NH—C(O)—CH₂—CH₂—, —CH₂—NH—C(O)—CH₂—CH₂,—CH₂—CH₂—NH—C(O)—CH₂—CH₂, —C(O)—NH—CH₂—, —C(O)—NH—CH₂—CH₂—,—O—C(O)—NH—CH₂—, —O—C(O)—N H—CH₂—CH₂—, —NH—CH₂—, —NH—CH₂—CH₂—,—CH₂—NH—CH₂—, —CH₂—CH₂—NH—CH₂—, —C(O)—CH₂—, —C(O)—CH₂—CH₂—,—CH₂—C(O)—CH₂—, —CH₂—CH₂—C(O)—CH₂—, —CH₂—CH₂—C(O)—CH₂—CH₂—,—CH₂—CH₂—C(O)—, —CH₂—CH₂—CH₂—C(O)—NH—CH₂—C H₂—NH—,—CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—C(O)—,—CH₂—CH₂—CH₂—C(O)—NH—CH₂—CH₂—NH—C(O)—CH₂—, bivalent cycloalkyl group,—N(R⁶)—, where R⁶ is H or an organic radical selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl and substituted aryl. An exemplarylinker is oxygen.

For purposes of the present disclosure, however, a group of atoms is notconsidered a spacer moiety when it is immediately adjacent to anoligomer segment, and the group of atoms is the same as a monomer of theoligomer such that the group would represent a mere extension of theoligomer chain.

The linkage “X” between the water-soluble oligomer and the opioidagonist is typically formed by reaction of a functional group on aterminus of the oligomer (or one or more monomers when it is desired to“grow” the oligomer onto the opioid agonist) with a correspondingfunctional group within the opioid agonist. For example, an amino groupon an oligomer may be reacted with a carboxylic acid or an activatedcarboxylic acid derivative on the opioid agonist, or vice versa, toproduce an amide linkage. Alternatively, reaction of an amine on anoligomer with an activated carbonate (e.g. succinimidyl or benzotriazylcarbonate) on the opioid agonist, or vice versa, forms a carbamatelinkage. Reaction of an amine on an oligomer with an isocyanate(R—N═C═O) on an opioid agonist, or vice versa, forms a urea linkage(R—NH—(C═O)—NH—R′). Further, reaction of an alcohol (alkoxide) group onan oligomer with an alkyl halide, or halide group within an opioidagonist, or vice versa, forms an ether linkage. In yet another couplingapproach, an opioid agonist having an aldehyde function is coupled to anoligomer amino group by reductive amination, resulting in formation of asecondary amine linkage between the oligomer and the opioid agonist.

In certain embodiments, the water-soluble oligomer is an oligomerbearing an aldehyde functional group. In this regard, the oligomer willhave the following structure: CH₃O—(CH₂—CH₂—O)_(n)—(CH₂)_(p)—C(O)H,wherein (n) is one of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10 and (p) is one of1, 2, 3, 4, 5, 6 and 7. In certain embodiments (n) values include 1, 2,3, 4, 7, 8, 9, and 10 and (p) values 2, 3 and 4. In addition, the carbonatom alpha to the —C(O)H moiety can optionally be substituted withalkyl.

Typically, the terminus of the water-soluble oligomer not bearing afunctional group is capped to render it unreactive. When the oligomerdoes include a further functional group at a terminus other than thatintended for formation of an opioid agonist compound, that group iseither selected such that it is unreactive under the conditions offormation of the linkage “X,” or it is protected during the formation ofthe linkage “X.” Such exemplary oligomeric termini include hydroxyl,alkoxy, and or a protecting group.

As stated above, the water-soluble oligomer includes at least onefunctional group prior to conjugation. The functional group typicallycomprises an electrophilic or nucleophilic group for covalent attachmentto an opioid agonist, depending upon the reactive group contained withinor introduced into the opioid agonist. Examples of nucleophilic groupsthat may be present in either the oligomer or the opioid agonist includehydroxyl, amine, hydrazine (—NHNH₂), hydrazide (—C(O)NHNH₂), and thiol.Preferred nucleophiles include amine, hydrazine, hydrazide, and thiol,particularly amine. Most opioid agonists for covalent attachment to anoligomer will possess a free hydroxyl, amino, thio, aldehyde, ketone, orcarboxyl group.

Examples of electrophilic functional groups that may be present ineither the oligomer or the opioid agonist include carboxylic acid,carboxylic ester, particularly imide esters, orthoester, carbonate,isocyanate, isothiocyanate, aldehyde, ketone, thione, alkenyl, acrylate,methacrylate, acrylamide, sulfone, maleimide, disulfide, iodo, epoxy,sulfonate, thiosulfonate, silane, alkoxysilane, and halosilane. Morespecific examples of these groups include succinimidyl ester orcarbonate, imidazoyl ester or carbonate, benzotriazole ester orcarbonate, vinyl sulfone, chloroethylsulfone, vinylpyridine, pyridyldisulfide, iodoacetamide, glyoxal, dione, mesylate, tosylate, andtresylate (2,2,2-trifluoroethanesulfonate).

Also included are sulfur analogs of several of these groups, such asthione, thione hydrate, thioketal, is 2-thiazolidine thione, etc., aswell as hydrates or protected derivatives of any of the above moieties(e.g. aldehyde hydrate, hemiacetal, acetal, ketone hydrate, hemiketal,ketal, thioketal, thioacetal).

An “activated derivative” of a carboxylic acid refers to a carboxylicacid derivative which reacts readily with nucleophiles, generally muchmore readily than the underivatized carboxylic acid. Activatedcarboxylic acids include, for example, acid halides (such as acidchlorides), anhydrides, carbonates, and esters. Such esters includeimide esters, of the general form —(CO)O—N[(CO)—]₂; for example,N-hydroxysuccinimidyl (NHS) esters or N-hydroxyphthalimidyl esters. Alsoincluded are imidazolyl esters and benzotriazole esters. Particularlypreferred are activated propionic acid or butanoic acid esters, asdescribed in co-owned U.S. Pat. No. 5,672,662. These include groups ofthe form —(CH₂)₂₋₃C(═O)O-Q, where Q is selected from N-succinimide,N-sulfosuccinimide, N-phthalimide, N-glutarimide,N-tetrahydrophthalimide, N-norbornene-2,3-dicarboximide, benzotriazole,7-azabenzotriazole, and imidazole.

Other electrophilic groups include succinimidyl carbonate, maleimide,benzotriazole carbonate, glycidyl ether, imidazoyl carbonate,p-nitrophenyl carbonate, acrylate, tresylate, aldehyde, and orthopyridyldisulfide.

These electrophilic groups are subject to reaction with nucleophiles,e.g. hydroxy, thio, or amino groups, to produce various bond types.Several of the electrophilic functional groups include electrophilicdouble bonds to which nucleophilic groups, such as thiols, can be added,to form, for example, thioether bonds. These groups include maleimides,vinyl sulfones, vinyl pyridine, acrylates, methacrylates, andacrylamides. Other groups comprise leaving groups that can be displacedby a nucleophile; these include chloroethyl sulfone, pyridyl disulfides(which include a cleavable S—S bond), iodoacetamide, mesylate, tosylate,thiosulfonate, and tresylate. Epoxides react by ring opening by anucleophile, to form, for example, an ether or amine bond. Reactionsinvolving complementary reactive groups such as those noted above on theoligomer and the opioid agonist are utilized to prepare the opioidagonist compounds of the invention.

In certain embodiments, reactions favor formation of a hydrolyticallystable linkage. For example, carboxylic acids and activated derivativesthereof, which include orthoesters, succinimidyl esters, imidazolylesters, and benzotriazole esters, react with the above types ofnucleophiles to form esters, thioesters, and amides, respectively, ofwhich amides are the most hydrolytically stable. Carbonates, includingsuccinimidyl, imidazolyl, and benzotriazole carbonates, react with aminogroups to form carbamates. Isocyanates (R—N═C═O) react with hydroxyl oramino groups to form, respectively, carbamate (RNH—C(O)—OR′) or urea(RNH—C(O)—NHR′) linkages. Aldehydes, ketones, glyoxals, diones and theirhydrates or alcohol adducts (i.e. aldehyde hydrate, hemiacetal, acetal,ketone hydrate, hemiketal, and ketal) are reacted with amines, followedby reduction of the resulting imine, if desired, to provide an aminelinkage (reductive amination).

In certain embodiment, reactions favor formation of a physiologicallycleavable linkage. The releasable linkages may, but do not necessarily,result in the water-soluble oligomer (and any spacer moiety) detachingfrom the opioid in vivo (and in some cases in vitro) without leaving anyfragment of the water-soluble oligomer (and/or any spacer moiety orlinker) attached to the opioid. Exemplary releasable linkages includecarbonate, carboxylate ester, phosphate ester, thiolester, anhydrides,acetals, ketals, acyloxyalkyl ether, imines, certain carbamates, andorthoesters. Such linkages can be readily formed by reaction of theopioid and/or the polymeric reagent using coupling methods commonlyemployed in the art. Hydrolyzable linkages are often readily formed byreaction of a suitably activated oligomer with a non-modified functionalgroup contained within the opioid.

In some instances the opioid agonist may not have a functional groupsuited for conjugation. In this instance, it is possible to modify the“original” opioid agonist so that it does have the desired functionalgroup. For example, if the opioid agonist has an amide group, but anamine group is desired, it is possible to modify the amide group to anamine group by way of a Hofmann rearrangement, Curtius rearrangement(once the amide is converted to an azide) or Lossen rearrangement (onceamide is concerted to hydroxamide followed by treatment withtolyene-2-sulfonyl chloride/base).

It is possible to prepare an opioid agonist compound of a parent opioidagonist bearing a carboxyl group wherein the carboxyl group-bearingopioid agonist is coupled to an amino-terminated oligomeric ethyleneglycol, to provide an opioid agonist compound having an amide groupcovalently linking the opioid agonist to the oligomer. This can beperformed, for example, by combining the carboxyl group-bearing opioidagonist with the amino-terminated oligomeric ethylene glycol in thepresence of a coupling reagent, (such as dicyclohexylcarbodiimide or“DCC”) in an anhydrous organic solvent.

Further, it is possible to prepare an opioid agonist compound of aparent opioid agonist bearing a hydroxyl group wherein the hydroxylgroup-bearing opioid agonist is coupled to an oligomeric ethylene glycolhalide to result in an ether (—O—) linked opioid agonist compound. Thiscan be performed, for example, by using sodium hydride to deprotonatethe hydroxyl group followed by reaction with a halide-terminatedoligomeric ethylene glycol.

In another example, it is possible to prepare an opioid agonist compounof a parent opioid agonist bearing a ketone group by first reducing theketone group to form the corresponding hydroxyl group. Thereafter, theopioid agonist now bearing a hydroxyl group can be coupled as describedherein.

In still another instance, it is possible to prepare an opioid agonistcompound of a parent opioid agonist bearing an amine group. In oneapproach, the amine group-bearing opioid agonist and an aldehyde-bearingoligomer are dissolved in a suitable buffer after which a suitablereducing agent (e.g., NaCNBH₃) is added. Following reduction, the resultis an amine linkage formed between the amine group of the aminegroup-containing opioid agonist and the carbonyl carbon of thealdehyde-bearing oligomer.

In another approach for preparing an opioid agonist compoun of a parentopioid agonist bearing an amine group, a carboxylic acid-bearingoligomer and the amine group-bearing opioid agonist are combined,typically in the presence of a coupling reagent (e.g., DCC). The resultis an amide linkage formed between the amine group of the aminegroup-containing opioid agonist and the carbonyl of the carboxylicacid-bearing oligomer.

The synthesis of certain exemplary opioid agonist compounds aredescribed in detail Example 1, Example 2, and Example 3. Example 1describes the synthesis of oligomeric mPEG_(n)-morphine compounds. Sincemorphine has two hydroxyl functions, in the synthesis employed, thenon-target hydroxyl group (i.e., the aromatic hydroxyl) is firstprotected with a suitable protecting group such as β-methoxyethoxymethylether, MEM, followed by reaction of the MEM-protected morphine witholigomeric PEG-mesylate (PEG_(n)-OMs) in the presence of the strongbase, sodium hydride, to introduce the oligomeric polyethylene glycolmoiety. The MEM protecting group is then removed by treatment with acid,e.g., hydrochloric acid, to provide the desired 6-mPEG_(n)-O-morphinecompounds (n=1, 2, 3, 4, 5, 6, 7, 9) having the generalized structureshown below:

The synthesis of illustrative mPEG_(n)-O-Codeine compounds is describedin detail in Example 2. In the approach employed, codeine, having asingle target hydroxyl function, is reacted with mPEG_(n) mesylate inthe presence of a strong base, e.g., sodium hydride, to provide thedesired compound. The products can be purified, for example, using highperformance liquid chromatography (HPLC). The oliogomericmPEG_(n)-O-Codeine compounds (n=1, 2, 3, 4, 5, 6, 7, 9) prepared havethe generalized structure shown below:

In a similar fashion, mPEG_(n)-O-hydroxycodone compounds were preparedas described in detail in Example 3 (n=1, 2, 3, 4, 5, 6, 7, 9). Thecompounds possess the following generalized structure:

Additional compounds may be similarly prepared.

In certain embodiments of the invention, X is a stable linker. Aspreviously disclosed, it has been found that certain opioid agonistsbound to small water-soluble oligomers via a stable linkage, whileretaining the ability to cross the blood-brain barrier, do so at areduced BBB crossing rate relative to the parent opioid agonist. Withoutwishing to be bound by any particular theory, it is believed that thereduced BBB membrane crossing rate is a direct function of changes inthe intrinsic BBB permeability properties of the molecule relative tothe parent opioid agonist. Again not wishing to be bound by anyparticular theory, it is presumed that such opioid agonist compoundspossess low addictive properties due to a slow crossing of the BBB,avoiding the rapid peak concentrations associated with the parent opioidagonists and underlying addictive highs. Additionally, the opioidagonist compounds may exhibit an improved side effect profile relativeto the parent opioid due to an altered tissue distribution of the opioidin vivo or decreased activity at peripheral opioid receptors. As such,the compositions and combinations of the present invention are believedto share these properties.

Thus, any combination of opioid agonist, linker, and water-solubleoligomer may be used, provided that the opioid agonist compound is ableto cross the BBB. In certain embodiments, the opioid agonist compoundcrosses the BBB at a reduced rate relative to the parent opioid agonist.In certain embodiments, the water-soluble oligomer is a PEG moiety. Incertain embodiments the PEG-moiety consists of 1-10 polyethylene glycolunits. Typically, the PEG moiety is a small monomeric PEG consisting of1-3 (i.e. 1, 2, or 3) polyethylene glycol units. In certain embodimentsthe PEG moiety may be 4 or 5 or 6 polyethylene glycol units.

With respect to the blood-brain barrier (“BBB”), this barrier restrictsthe transport of drugs from the blood to the brain. This barrierconsists of a continuous layer of unique endothelial cells joined bytight junctions. The cerebral capillaries, which comprise more than 95%of the total surface area of the BBB, represent the principal route forthe entry of most solutes and drugs into the central nervous system.

As will be understood by one of skill in the art, molecular size,lipophilicity, and PgP interaction are among the primary parametersaffecting the intrinsic BBB permeability properties of a given molecule.That is to say, these factors, when taken in combination, controlwhether a given molecule passes through the BBB, and if so, at whatrate.

Due to the small pore size within the BBB, molecular size plays asignificant role in determining whether a given molecule will passthrough the BBB. Very large molecules, for example a molecule having amolecular weight of 5,000 Daltons, will not cross the BBB, whereas smallmolecules are more likely to permeate the BBB. Other factors, however,also play a role in BBB crossing. Antipyrine and atenolol are both smallmolecule drugs; antipyrine readily crosses the BBB, whereas passage ofatenolol is very limited, or effectively non-existent. Antipyrine is anindustry standard for a high BBB permeation; atenolol is an industrystandard for low permeation of the BBB. See, e.g., Summerfield et al., JPharmacol Exp Ther 322:205-213 (2007). Therefore, in accordance with theinvention, where X is a stable linker, opioid agonist compounds, as partof the disclosed compositions and combinations, having 1-3 polyethyleneglycol units can generally be expected to cross the BBB. In certaincircumstances, where the intrinsic BBB permeability properties as awhole are suitable, particular opioid agonist compounds having 4 or 5polyethylene glycol units may also cross the BBB.

Lipophilicity is also a factor in BBB permeation. Lipophilicity may beexpressed as logP (partition coefficient) or in some instances logD(distribution coefficient). The logP (or logD) for a given molecule canbe readily assessed by one of skill in the art. The value for logP maybe a negative number (more hydrophilic molecules) or a positive number(more hydrophobic molecules). As used herein when referring to logP,“more negative” means moving in the direction, on the logP scale, frompositive to negative logP (e.g., a logP of 2.0 is “more negative” than alogP of 4.0, a logP of −2.0 is “more negative” than a logP of −1.0).Molecules having a negative logP (hydrophilic molecules) generally donot permeate the BBB. In certain embodiments, the opioid agonistcompounds of the invention have a logP between about 0 and about 4.0. Incertain embodiments, the opioid agonist compounds of the invention havea logP between about 1.0 and about 3.5. In certain embodiments, theopioid agonist compounds of the invention have a logP of about 4.0, ofabout 3.5, of about 3.0, of about 2.5, of about 2.0, of about 1.5, ofabout 1.0, of about 0.5, or of about 0, or they may have a logP in therange of about 0 to about 3.5, of about 0 to about 3.0, of about 0 toabout 2.0, of about 0 to about 1.0, of about 1.0 to about 4.0, of about1.0 to about 3.0, of about 1.0 to about 2.0, of about 2.0 to about 4.0,of about 2.0 to about 3.5, of about 2.0 to about 3.0, of about 3.0 toabout 4.0, or of about 3.0 to about 3.5.

Permeability across the BBB is also dependent on P-glycoprotein, or PgP,an ATP-dependent efflux transporter highly expressed at the BBB. One ofskill in the art can readily determine whether a compound is a substratefor PgP using in vitro methods. Compounds which are substrates for PgPin vitro likely will not permeate the BBB in vivo. Conversely, poorsubstrates for PgP, as assessed in vitro, are generally likely todisplay in vivo permeability of the BBB, provided the compound meetsother criteria as discussed herein and as known to one of skill in theart. See, e.g., Tsuji, NeuroRx 2:54-62 (2005) and Rubin and Staddon,Annu. Rev. Neurosci. 22:11-28 (1999).

In certain embodiments, the water-soluble oligomer may be selected inaccordance with the desired pharmacokinetic profile of the opioidagonist compound. In other words, conjugation of the opioid to awater-soluble oligomer will result in a net reduction in BBB membranecrossing rate, however the reduction in rate may vary depending on thesize of the oligomer used. Generally, where a minimal reduction in BBBcrossing rate is desired, a smaller oligomer may be used; where a moreextensive reduction in BBB crossing rate is desired, a larger oligomermay be used. In certain embodiments, a combination of two or moredifferent opioid agonist compounds may be administered simultaneously,wherein each opioid agonist compound has a differently sizedwater-soluble oligomer portion, and wherein the rate of BBB crossing foreach opioid agonist compound is different due to the different oligomersizes. In this manner, the rate and duration of BBB crossing of theopioid agonist compound can be specifically controlled through thesimultaneous administration of multiple opioid agonist compounds withvarying pharmacokinetic profiles.

For compounds whose degree of blood-brain barrier crossing ability isnot readily known, such ability can be determined using a suitableanimal model such as an in situ rat brain perfusion (“RBP”) model.Briefly, the RBP technique involves cannulation of the carotid arteryfollowed by perfusion with a compound solution under controlledconditions, followed by a wash out phase to remove compound remaining inthe vascular space. (Such analyses can be conducted, for example, bycontract research organizations such as Absorption Systems, Exton, Pa.).More specifically, in the RBP model, a cannula is placed in the leftcarotid artery and the side branches are tied off. A physiologic buffercontaining the analyte (typically but not necessarily at a 5 micromolarconcentration level) is perfused at a flow rate of about 10 mL/minute ina single pass perfusion experiment. After 30 seconds, the perfusion isstopped and the brain vascular contents are washed out withcompound-free buffer for an additional 30 seconds. The brain tissue isthen removed and analyzed for compound concentrations via liquidchromatograph with tandem mass spectrometry detection (LC/MS/MS).Alternatively, blood-brain barrier permeability can be estimated basedupon a calculation of the compound's molecular polar surface area(“PSA”), which is defined as the sum of surface contributions of polaratoms (usually oxygens, nitrogens and attached hydrogens) in a molecule.The PSA has been shown to correlate with compound transport propertiessuch as blood-brain barrier transport. Methods for determining acompound's PSA can be found, e.g., in, Ertl, P., et al., J. Med. Chem.2000, 43, 3714-3717; and Kelder, J., et al., Pharm. Res. 1999, 16,1514-1519.

In certain embodiments, where X is a stable linker, the molecular weightof the opioid agonist compound is less than 2000 Daltons, and in certainembodiments less than 1000 Daltons. In certain embodiments, themolecular weight of the opioid agonist compound is less than 950Daltons, less than 900 Daltons, less than 850 Daltons, less than 800Daltons, less than 750 Daltons, less than 700 Daltons, less than 650Daltons, less than 600 Daltons, less than 550 Daltons, less than 500Daltons, less than 450 Daltons, or less than 400 Daltons.

In certain embodiments, where X is a stable linker, the molecular weightof X-POLY (i.e. the water soluble oligomer in combination with thelinker, where present) is less than 2000 Daltons. In certainembodiments, the molecular weight of the X-POLY is less than 1000Daltons. In certain embodiments, the molecular weight of X-POLY is lessthan 950 Daltons, less than 900 Daltons, less than 850 Daltons, lessthan 800 Daltons, less than 750 Daltons, less than 700 Daltons, lessthan 650 Daltons, less than 600 Daltons, less than 550 Daltons, lessthan 500 Daltons, less than 450 Daltons, less than 400 Daltons, lessthan 350 Daltons, less than 300 Daltons, less than 250 Daltons, lessthan 200 Daltons, less than 150 Daltons, less than 100 Daltons, or lessthan 50 Daltons.

In certain embodiments, where X is a stable linker, the opioid agonistcompound (i.e. OPIOID-X-POLY) is less hydrophobic than the parentopioid. In other words, the logP of the opioid agonist compound is morenegative than the logP of the parent opioid agonist. In certainembodiments, the logP of the opioid agonist compound is about 0.5 unitsmore negative than that of the parent opioid agonist. In certainembodiments, the log P of the opioid agonist compound is about 4.0 unitsmore negative, about 3.5 units more negative, about 3.0 units morenegative, about 2.5 units more negative, about 2.0 units more negative,about 1.5 units more negative, about 1.0 units more negative, about 0.9units more negative, about 0.8 units more negative, about 0.7 units morenegative, about 0.6 units more negative, about 0.4 units more negative,about 0.3 units more negative, about 0.2 units more negative or about0.1 units more negative than the parent opioid agonist. In certainembodiments, the logP of the opioid agonist compound is about 0.1 unitsto about 4.0 units more negative, about 0.1 units to about 3.5 unitsmore negative, about 0.1 units to about 3.0 units more negative, about0.1 units to about 2.5 units more negative, about 0.1 units to about 2.0units more negative, about 0.1 units to about 1.5 units more negative,about 0.1 units to about 1.0 units more negative, about 0.1 units toabout 0.5 units more negative, about 0.5 units to about 4.0 units morenegative, about 0.5 units to about 3.5 units more negative, about 0.5units to about 3.0 units more negative, about 0.5 units to about 2.5units more negative, about 0.5 units to about 2.0 units more negative,about 0.5 units to about 1.5 units more negative, about 0.5 units toabout 1.0 units more negative, about 1.0 units to about 4.0 units morenegative, about 1.0 units to about 3.5 units more negative, about 1.0units to about 3.0 units more negative, about 1.0 units to about 2.5units more negative, about 1.0 units to about 2.0 units more negative,about 1.0 units to about 1.5 units more negative, about 1.5 units toabout 4.0 units more negative, about 1.5 units to about 3.5 units morenegative, about 1.5 units to about 3.0 units more negative, about 1.5units to about 2.5 units more negative, about 1.5 units to about 2.0units more negative, about 2.0 units to about 4.0 units more negative,about 2.0 units to about 3.5 units more negative, about 2.0 units toabout 3.0 units more negative, about 2.0 units to about 2.5 units morenegative about 2.5 units to about 4.0 units more negative, about 2.5units to about 3.5 units more negative, about 2.5 units to about 3.0units more negative, about 3.0 units to about 4.0 units more negative,about 3.0 units to about 3.5 units more negative, or about 3.5 units toabout 4.0 units more negative than the parent opioid agonist. In someembodiments, the logP of the opioid agonist compound is the same as, oris more positive than, the logP of the parent opioid agonist.

The relative permeability across the blood brain barrier and brainplasma ratio of the opioid agonist compounds has been described, forexample, in International Patent Application Publication No. WO2011/088140.

In certain embodiments, where X is a stable linker, the opioid agonistcompound retains a suitable affinity for its target receptor(s), and byextension a suitable concentration and potency within the brain. Incertain embodiments the opioid agonist compound binds, at least in part,to the same receptor(s) to which the parent opioid agonist binds. Todetermine whether the parent opioid agonist or the opioid agonistcompound has activity as mu, kappa, or delta opioid receptor agonist,for example, it is possible to test such a compound. For example, aradioligand binding assay in CHO cells that heterologously express therecombinant human mu, kappa, or delta opioid receptor can be used.Briefly, cells are plated in 24 well plates and washed with assaybuffer. Competition binding assays are conducted on adherent whole cellsincubated with increasing concentrations of opioid agonist compounds inthe presence of an appropriate concentration of radioligand.^([3)H]naloxone, ^([3)H]diprenorphine and ^([3)H]DPDPE are used as thecompeting radioligands for mu, kappa and delta receptors respectively.Following incubation, cells are washed, solubilized with NaOH and boundradioactivity is measured using a scintillation counter.

In certain embodiments, the K₁ values of the opioid agonist compoundsindividually fall within the range of 0.1 to 900 nM, in certainembodiments within the range of 0.1 and 300 nM, and in certainembodiments within the range of 0.1 and 50 nM. In certain embodiments,where X is a stable linker, there is no loss of affinity of the opioidagonist compound (i.e. the OPIOID of OPIOID-X-POLY) relative to theaffinity of OPIOID to its target receptor(s), and in certain embodimentsthe affinity of the opioid agonist compound may be greater than theaffinity of OPIOID to its target receptor(s). In certain embodiments,where X is a stable linker, the affinity of the opioid agonist compound(i.e. the OPIOID of OPIOID-X-POLY) is reduced minimally relative to theaffinity of OPIOID to its target receptor(s), and in some cases may evenshow an increase in affinity or no change in affinity. In certainembodiments, there is less than about a 2-fold loss of affinity of theopioid agonist compound relative to the affinity of the parent opioidagonist for its target receptor(s). In certain embodiments, there isless than about a 5-fold loss, less than about a 10-fold loss, less thanabout a 20-fold loss, less than about a 30-fold loss, less than about a40-fold loss, less than about a 50-fold loss, less than about a 60-foldloss, less than about a 70-fold loss, less than about an 80-fold loss,less than about a 90-fold loss, or less than about a 100-fold loss ofaffinity of the opioid agonist compound relative to the affinity of theparent opioid agonist for its target receptor(s).

In certain other embodiments where X is a stable linker, the reductionin affinity of the opioid agonist compound relative to the affinity ofthe parent opioid agonist for its target receptor(s) is less than 20%.In certain embodiments, the reduction in affinity of the opioid agonistcompound relative to the parent opioid is less than 10%, less than 30%,less than 40%, less than 50%, less than 60%, less than 70%, less than80%, less than 90%, or less than 95%.

In certain embodiments where X is a stable linker, the rate of crossingthe BBB, or the permeability of the opioid agonist compound is less thanthe rate of crossing of OPIOID alone. In certain embodiments, the rateof crossing is at least about 50% less than the rate of OPIOID alone. Incertain embodiments, there is at least about a 10% reduction, at leastabout a 15% reduction, at least about a 20% reduction, at least about a25% reduction, at least about a 30% reduction, at least about a 35%reduction, at least about a 40% reduction, at least about a 45%reduction, at least about a 55% reduction, at least about a 60%reduction, at least about a 65% reduction, at least about a 70%reduction, at least about a 75% reduction, at least about an 80%reduction, at least about an 85% reduction, at least about a 90%reduction at least about a 95% reduction, or at least about a 99%reduction in the BBB crossing rate of the opioid agonist compoundrelative to the rate of crossing of OPIOID alone. In other embodiments,the opioid agonist compounds of the invention may exhibit a 10-99%reduction, a 10-50% reduction, a 50-99% reduction, a 50-60% reduction, a60-70% reduction, a 70-80% reduction, an 80-90% reduction, or a 90-99%reduction in the BBB crossing rate of the opioid agonist compoundrelative to the rate of crossing of OPIOID alone.

The opioid agonist compounds used in the present compositions andcombinations, where X is a stable linker, may exhibit a 1 to 100 foldreduction in the BBB crossing rate relative to the rate of crossing ofthe OPIOID alone. In certain embodiments, there may be at least about a2-fold loss, at least about a 5-fold loss, at least about a 10-foldloss, at least about a 20-fold loss, at least about a 30-fold loss, atleast about a 40-fold loss, at least about a 50-fold loss, at leastabout a 60-fold loss, at least about a 70-fold loss, at least about an80-fold loss, at least about a 90-fold loss, or at least about a100-fold loss in the BBB crossing rate of the opioid agonist compoundrelative to the BBB crossing rate of the parent opioid agonist.

The rate of BBB crossing of the opioid agonist compounds, where X is astable linker, may also be viewed relative to the BBB crossing rate ofantipyrine (high permeation standard) and/or atenolol (low permeationstandard). It will be understood by one of skill in the art that impliedin any reference to BBB crossing rates of the opioid agonist compoundsof the invention relative to the BBB crossing rate of antipyrine and/oratenolol is that the rates were evaluated in the same assay, under thesame conditions. Thus, in certain embodiments opioid agonist compoundsused herein may exhibit at least about a 2-fold lower, at least about a5-fold lower, at least about a 10-fold lower, at least about a 20-foldlower, at least about a 30-fold lower, at least about a 40-fold lower,at least about a 50-fold lower, at least about a 60-fold lower, at leastabout a 70-fold lower, at least about an 80-fold lower, at least about a90-fold lower, or at least about a 100-fold lower rate of BBB crossingrate relative to the BBB crossing rate of antipyrine. In otherembodiments, the opioid agonist compounds of the invention, may exhibitat least about a 2-fold greater, at least about a 5-fold greater, atleast about a 10-fold greater, at least about a 20-fold greater, atleast about a 30-fold greater, at least about a 40-fold greater, atleast about a 50-fold greater, at least about a 60-fold greater, atleast about a 70-fold greater, at least about an 80-fold greater, atleast about a 90-fold greater, or at least about a 100-fold greater rateof BBB crossing rate relative to the BBB crossing rate of atenolol.

In certain embodiments, where X is a stable linker, the opioid agonistcompound (i.e. OPIOID-X-POLY) may retain all or some of the opioidagonist bioactivity relative to the parent opioid (i.e. OPIOID). Incertain embodiments, the opioid agonist compound retains all the opioidagonist bioactivity relative to the parent opioid, or in somecircumstances, is even more active than the parent opioid. In certainembodiments, the opioid agonist compounds used herein exhibit less thanabout a 2-fold decrease, less than about a 5-fold decrease, less thanabout a 10-fold decrease, less than about a 20-fold decrease, less thanabout a 30-fold decrease, less than about a 40-fold decrease, less thanabout a 50-fold decrease, less than about a 60-fold decrease, less thanabout a 70-fold decrease, less than about an 80-fold decrease, less thanabout a 90-fold decrease, or less than about a 100-fold decrease inbioactivity relative to the parent opioid agonist. In some embodiments,the opioid agonist compound retains at least 1%, at least 2%, at least3%, at least 4%, at least 5%, at least 6%, at least 7%, at least 8%, atleast 9%, at least 10%, at least 20%, at least 30%, at least 40%, atleast 50%, at least 60%, at least 70%, at least 75%, at least 80%, atleast 85%, at least 90%, or at least 95% of the opioid agonistbioactivity relative to the parent opioid.

It will be understood by one of skill in the art that the values recitedherein are exemplary and non-limiting, and that certain opioid agonistcompounds may fall outside the ranges recited herein yet remain withinthe spirit and scope of the invention. Opioid agonist compounds may beprepared and tested as a matter of routine experimentation for one ofskill in the art. In particular, opioid agonists, bound to awater-soluble oligomer via a stable linkage, may be tested forpenetration of the blood brain barrier as described above. Thus one ofskill in the art can readily ascertain whether an opioid agonistcompound is able to cross the BBB.

While it is believed that the full scope of the opioid agonist compoundsof these embodiments of the invention has been described, an optimallysized oligomer can be determined as follows.

First, an oligomer obtained from a monodisperse or bimodal water-solubleoligomer is coupled to the opioid agonist through a stable linkage.Next, in vitro retention of activity is analyzed. The ability of theopioid agonist compound to cross the blood-brain barrier is thendetermined using an appropriate model and compared to that of theunmodified parent opioid agonist. If the results are favorable, that isto say, if, for example, the rate of crossing is reduced to anappropriate degree, then the bioactivity of opioid agonist compound isfurther evaluated. In certain embodiments, the compounds according tothe invention maintain a significant degree of bioactivity relative tothe parent opioid agonist, i.e., greater than about 30% of thebioactivity of the parent opioid agonist, or greater than about 50% ofthe bioactivity of the parent opioid agonist. In certain embodiments,the opioid agonist compound is orally bioavailable.

The above steps are repeated one or more times using oligomers of thesame monomer type but having a different number of subunits and theresults are compared.

For each opioid agonist compound whose ability to cross the blood-brainbarrier is appropriately reduced in comparison to the parent opioidagonist, its oral bioavailability is then assessed. Based upon theseresults, that is to say, based upon the comparison of opioid agonistcompounds having oligomers of varying size to a given opioid agonist ata given position or location within the opioid agonist, it is possibleto determine the size of the oligomer most effective in providing anopioid agonist compound having an optimal balance between appropriatereduction in biological membrane crossing, oral bioavailability, andbioactivity. The small size of the oligomers makes such screeningsfeasible, and allows one to effectively tailor the properties of theresulting opioid agonist compound. By making small, incremental changesin oligomer size, and utilizing an experimental design approach, one caneffectively identify an opioid agonist compound having a favorablebalance of reduction in biological membrane crossing rate, bioactivity,and oral bioavailability. In some instances, attachment of an oligomeras described herein is effective to actually increase oralbioavailability of the opioid agonist.

For example, one of ordinary skill in the art, using routineexperimentation, can determine a best suited molecular size and linkagefor improving oral bioavailability by first preparing a series ofoligomers with different weights and functional groups and thenobtaining the necessary clearance profiles by administering the opioidagonist compounds to a patient and taking periodic blood and/or urinesampling. Once a series of clearance profiles have been obtained foreach tested opioid agonist compound, a suitable opioid agonist compoundcan be identified.

Animal models (rodents and dogs) can also be used to study oral drugtransport. In addition, non-in vivo methods include rodent everted gutexcised tissue and Caco-2 cell monolayer tissue-culture models. Thesemodels are useful in predicting oral drug bioavailability.

In certain embodiments of the invention, X is a physiologicallycleavable linker. As disclosed in the art, it has been found thatcertain opioids bound to small water-soluble oligomers via a cleavablelinkage are unable to cross the BBB, and therefore exhibit a net reducedBBB membrane crossing rate due to slow physiological cleavage of theopioid from the water-soluble oligomer. In particular, X may be selectedin accordance with the desired pharmacokinetic profile of the parentopioid agonist. In other words, conjugation of the opioids to awater-soluble oligomer will result in a net reduction in BBB membranecrossing rate, however the reduction in rate may vary depending on thelinker used. Where a minimal reduction in BBB crossing rate is desired,X may be a rapidly degraded linker; where an extensive reduction in BBBcrossing rate is desired, X may be a more slowly degraded linker. Incertain embodiments, a combination of two or more different opioidagonist compounds may be administered simultaneously, wherein eachopioid agonist compound has a different linker X, and wherein the rateof degradation of each X is different. In other words, for eachdifferent compound, the opioid will be cleaved from the water-solubleoligomer at a different rate, resulting in different net BBB membranecrossing rates. A similar effect may be achieved through the use ofmultifunctional water-soluble oligomers having two or more sites ofopioid attachment, with each opioid linked to the water-soluble oligomerthrough linkers having varying rates of degradation. In this manner, therate and duration of BBB crossing of the opioid agonist compound can bespecifically controlled through the simultaneous administration ofmultiple opioid agonist compounds with varying pharmacokinetic profiles.

Not wishing to be bound by any particular theory, it is presumed thatsuch opioid agonist compounds possess low addictive properties due tothe net slow crossing of the BBB (due to slow physiological cleavagefollowing administration of the opioid agonist compound), avoiding therapid peak concentrations associated with parent opioid agonists andunderlying addictive highs. Again, not wishing to be bound by anyparticular theory, it is believed that the opioid agonist compounds ofthe invention circulate in the plasma, and are cleaved in vivo at a ratedependent upon the specific cleavable linker used (and, forenzymatically degradable linkers, enzyme concentration and affinity),such that the concentration of the parent opioid circulating in theperiphery is generally very low due to the slow rate of cleavage. Oncecleavage has occurred, the parent opioid may travel to the brain tocross the BBB; the slow release of the parent opioid through cleavageresults in a net slow delivery of the parent opioid to the brain.Additionally, the opioid agonist compounds of the present inventionexhibit an improved side effect profile relative to the parent opioiddues to an altered tissue distribution of the opioid in vivo and alteredreceptor interaction at the periphery.

Moreover, in accordance with these embodiments of the invention, anycombination of opioid, linker, and water-soluble oligomer may be used,provided that the opioid agonist compound is not able to cross the BBBor only a small fraction of the opioid agonist compound, in certainembodiments less than 5% of that administered, is able to cross the BBB.In certain embodiments, the opioid agonist compound is not able to crossthe BBB. In certain embodiments, the opioid portion of the molecule, dueto physiological cleavage of the opioid agonist compound, crosses theBBB at a net reduced rate relative to the parent opioid agonist. Incertain embodiments, the water-soluble oligomer is a PEG moiety. Incertain embodiments, the PEG moiety is a small monomeric PEG consistingof at least 6 polyethylene glycol units, preferably 6-35 polyethyleneglycol units. In certain embodiments, the PEG moiety may be 6-1825polyethylene glycol units.

In certain embodiments, where X is a physiologically cleavable linker,the opioid agonist compound (i.e. OPIOID-X-POLY) may or may not bebioactive. In certain embodiments, the opioid agonist compound is notbioactive. Such an opioid agonist compound is nevertheless effectivewhen administered in vivo to a mammalian subject in need thereof, due torelease of the opioid from the opioid agonist compound subsequent toadministration. In certain embodiments, the opioid agonist compounds ofthe invention exhibit greater than about a 10-fold decrease, greaterthan about a 20-fold decrease, greater than about a 30-fold decrease,greater than about a 40-fold decrease, greater than about a 50-folddecrease, greater than about a 60-fold decrease, greater than about a70-fold decrease, greater than about an 80-fold decrease, greater thanabout a 90-fold decrease, greater than about a 95-fold decrease, greaterthan about a 97-fold decrease, or greater than about a 100-fold decreasein bioactivity relative to the parent opioids. In some embodiments, theopioid agonist compound retains less than 1%, less than 2%, less than3%, less than 4%, less than 5%, less than 10%, less than 15%, less than20%, less than 25%, less than 30%, less than 35%, less than 40%, lessthan 50%, less than 60%, less than 70%, less than 80% or less than 90%of the opioid agonist bioactivity relative to the parent opioid.

In certain embodiments where X is a physiologically cleavable linker,the affinity of OPIOID-X-POLY for the opioid target receptor issubstantially reduced relative to the affinity of OPIOID to its targetreceptor. In certain embodiments, there is at least about a 2-fold lossof affinity of the opioid agonist compound relative to the affinity ofthe parent opioid or its target receptor(s). In certain embodiments,there is at least about a 5-fold loss, at least about a 10-fold loss, atleast about a 20-fold loss, at least about a 30-fold loss, at leastabout a 40-fold loss, at least about a 50-fold loss, at least about a60-fold loss, at least about a 70-fold loss, at least about an 80-foldloss, at least about a 90-fold loss, or at least about a 100-fold lossof affinity of the opioid agonist compound relative to the affinity ofthe parent opioid agonist for its target receptor(s).

In certain embodiments where X is a physiologically cleavable linker,the reduction in affinity of the opioid agonist compound relative to theaffinity of the parent opioid for its target receptor(s) is at least20%. In certain embodiments, the reduction in affinity of the opioidagonist compound relative to the parent opioid is at least 10%, at least30%, at least 40%, at least 50%, at least 60%, at least 70%, at least80%, at least 90%, or at least 95%.

As previously noted, in certain embodiments where X is a physiologicallycleavable linker, the opioid agonist compound is not bioactive. Such anopioid agonist compound represents a prodrug, where the compound asadministered is inactive, and is made active subsequent toadministration through physiological processes. Thus, in certainembodiments, the invention provides a prodrug comprising an opioidagonist reversibly attached via a covalent bond to a releasable moiety,wherein a given molar amount of the prodrug administered to a patientexhibits a rate of accumulation and a C_(max) of the opioid agonist inthe central nervous system in the mammal that is less than the rate ofaccumulation and the C_(max) of an equal molar amount of the opioidagonist had the opioid agonist not been administered as part of aprodrug. The releasable moiety may be a water-soluble oligomer, and incertain embodiments is a polyethylene glycol oligomer. The agonist maybe a mu, kappa, or delta opioid agonist.

In certain embodiments of the invention, X is a physiologicallycleavable linker and POLY is a small monomeric PEG consisting of 1-5(i.e. 1, 2, 3, 4, or 5) polyethylene glycol units, and in certainembodiments, 1-3 (i.e. 1, 2, or 3) polyethylene glycol units. Suchcompounds are small enough to cross the blood-brain barrier, but do soat a reduced membrane crossing rate relative to the parent opioid, andas such possess low addictive properties as previously discussed. Incertain embodiments, X is selected to provide for cleavage of the linkerand release of the opioid agonist subsequent to crossing the BBB.Alternatively, cleavage of the linker may happen both prior to, andafter, crossing the BBB; in this manner the rate and duration of BBBcrossing of the opioid agonist and/or opioid agonist compound can bespecifically controlled.

Under the World Health Organization nomenclature, dependence syndrome(also referred to as withdrawal syndrome) is defined as a state, psychicand sometimes also physical, resulting from the interaction between aliving organism and a drug, characterized by behavioral and otherresponses that always include a compulsion to take the drug on acontinuous or periodic basis in order to experience its psychic effects,and sometimes to avoid the discomfort of its absence (WHO ExpertCommittee on Drug Dependence. 28^(th) Report. Geneva, Switzerland: WHO1993). The International Classification of Diseases or ICD-10 uses aslightly different standard to assess dependence syndrome (WHO. TheICD-10 Classification of Mental and Behavioral Disorders: ClinicalDescriptions and Diagnostic Guidelines. Geneva, Switzerland: WHO, 1992).The ICD-10 uses the term “dependence syndrome” when at least 3 of the 6features are identified with dependence syndrome. Of the six criteria,four relate to compulsivity: i) a persistent, strong desire to take adrug; ii) difficulty controlling drug use; iii) impairment of function,including neglect of pleasures and interests; and iv) harm to self. Theremaining two factors relate to evidence of withdrawal symptoms andtolerance.

Studies to assess potential opioid misuse in humans may be carried outusing, for example, one or more screening questionnaires designed toscreen for such risk of opioid medication misuse. A number of screeningtests have been developed to assess a patients' susceptibility to drugmisuse or current misuse, abuse, or addition to opioid drugs. Anoverview of such screening tests is provided in Manchikanti, L., et al.,Pain Physician 2008; Opioids Special Issue: 11:S155-S180. Any one ormore of the screening tests described therein may be useful inevaluating a patient's tendency towards or current abuse of opioid drugsin the management and treatment of pain. One particularly useful tool topredict potential substance misuse in pain patients is described inAtluri and Sudarshan (Atluri S L, Sudarshan, G. Pain Physician 2004;7:333-338). Another example of a useful screening tool is the PainMedication Questionnaire or PMQ (Adams, L., 27 et al., J. Pain andSymptom Management, (5), 440-459 (2004)), among others. Commonly usedcriteria for evaluation of drug abuse include an evaluation of excessiveopioid needs (e.g., multiple dose escalations, multiple emergency roomvisits, multiple calls to obtain more opiates, and the like), deceptionor lying to obtain controlled substances, current or prior doctorshopping, etc. Also indicative of a potential for addiction or abuse isthe exaggeration of pain by the subject, or an unclear etiology of thepain.

One biological method for screening or monitoring opioid use is urineanalysis. Although opioid testing may be carried out on urine, serum, orfor example, hair, urine analysis is typically carried out due to itsrelatively good specificity, sensitivity, ease of administration, andcost. Such screening can be carried out at the beginning of treatment toestablish a baseline, and/or to detect the presence of opioids and/orother drugs, and during the course of treatment to ensure compliance(i.e., to detect the prescribed medication), or misuse (i.e., overuse)of the prescribed medication, and to identify substances that are not tobe expected in the urine. Two illustrative urine drug tests that may beused include immunoassay drug testing (“dipstick testing”) andlaboratory-based specific drug identification using gaschromatography/mass spectrometry and high performance liquidchromatography. Any of a variety of acceptable monitoring methods may beused to assess the potential for abuse/addiction potential of thesubject opioid agonist compounds and compositions comprising the subjectopioid agonist compounds.

In addition to demonstrating analgesic activity, the opioid agonistcompounds used herein advantageously display very low abuse potential inpreclinical studies in monkeys and in rats using self-administration anddrug discrimination protocols as described in International PatentApplication Publication No. WO 2011/088140. As described therein,squirrel monkeys with indwelling intravenous (IV) catheters were trainedin standard lever-press methods using morphine prior to testing withtest articles using a schedule of reinforcement in daily sessions of 90minutes. Dose-related effects of the test articles were examined, usingtwo or more doses of each drug in 3-4 subjects in a double alternationschedule in which each unit dose (or vehicle) was used in twoconsecutive sessions before a change in unit dose. In theself-administration studies in monkeys, the illustrative oligomeric PEGopioid agonist compound, mPEG₆-O-hydroxycodone, displayed significantlylower potency than oxycodone and morphine, and showed a marked reductionin reinforcing strength at the highest doses tested of 3.2mg/kg/injection. Specifically, morphine and oxycodone produced 100%injection lever responses (% ILR) at doses of 0.03 mg/kg/injection and0.1 mg/kg/injection, respectively. By contrast, the oligomericmPEG-opioid agonist compound produced exclusive injection leverresponding in only two subjects at the highest dose tested, 3.2mg/kg/injection. The compound produced 22%, 39% and 50% ILR at 0.32, 1.0and 3.2 mg/kg, respectively.

Additionally, as described in International Patent ApplicationPublication No. WO 2011/088140, in the three-day rat substitution tests,rats trained to self-administer cocaine were exposed to saline or testarticle via intravenous bolus infusions for one hour sessions on threeconsecutive days. A compound was considered to exhibit reinforcingproperties if animals maintained lever press responding with less than20% variability over three consecutive sessions. Progressive ratiostudies were performed by progressively increasing the number of leverpresses needed to result in drug delivery and the break point is definedas the number of lever-presses at which the animal no longer presses inorder to achieve the drug reward.

In self-administration studies in rats, the representative compound,mPEG₆-O-hydroxycodone, produced no behavioral evidence of positivereinforcement when tested at doses of up to 3.2 mg/kg/injection, usingthree-day substitution tests and progressive ratio tests oncocaine-trained animals. The PEG-opioid agonist compound showed noreinforcing properties and behaved like saline in progressive ratiotests in rats. Five out of six tested doses of the compound generatedprogressive ratio breakpoints lower than that produced by saline. Bycontrast, the maintenance dose of cocaine (0.56 mg/kg/infusion) produceda breakpoint of 128 responses for the delivery of a single bolus ofdrug. Likewise, hydrocodone, at a dose of 0.18 mg/kg/infusion, produceda breakpoint of 114, whereas oxycodone at test doses of 0.01 and 0.032mg/kg/infusion produced mean breakpoints respectively of 56 and 79.

Thus, the opioid agonist compounds used herein, in addition todemonstrating antinociceptive properties, demonstrate a marked reductionin self-administration in primates, which is a key indicator of abuseliability for drugs. It is expected that when combined with a secondanalgesic, these properties will remain present. In one or more of themethods provided herein, an opioid agonist compound in combination withan analgesic, is characterized as producing a measurable reduction inaddiction potential over the parent opioid agonist when valuated in anin-vivo self-administration model in rodents or primates as described inInternational Patent Application Publication No. WO 2011/088140.

The opioid agonist compounds described herein, in addition to possessinganalgesic properties, and having the ability to reduce addiction/abusepotential associated with administration of opioids, have beendiscovered to also reduce one or more CNS side-effects typicallyassociated with administration of opioid drugs. As such, it is believedthat those properties will remain when the opioid agonist compounds areadministered in combination with an analgesic. Thus, provided herein isa method for reducing one or more CNS-side effects related to theadministration of an opioid analgesic drug by administering an opioidagonist compound as provided herein in combination with an analgesic.Also provided herein is a method for reducing the addiction potentialand simultanetously reducing one or more CNS-side effects related toadministration of an opioid analgesic drug by administering to a subjectsuffering from pain a therapeutically effective amount of an opioidagonist compound as provided herein in combination with an analgesic.

In one or more embodiments of the method(s), an opioid agonist compoundas provided herein is considered to be effective in reducing one or moreCNS-related side effects related to administration of the opioidanalgesic drug if the opioid agonist compound exhibits a ten-fold orgreater reduction in at least one CNS-related side effect associatedwith administration of the parent opioid agonist when evaluated in amouse or other suitable animal model at an equivalent dose, wherein theone or more CNS-related side effects/elicited behaviors is selected fromstraub tail response, locomotor ataxia, tremor, hyperactivity,hypoactivity, convulsions, hindlimb splay, muscle rigidity, pinnareflex, righting reflex and placing. As such, it is believed that thoseproperties will remain when the opioid agonist compounds areadministered in combination with an analgesic. One particularly usefulindicator for CNS activity is the straub-tail response, although any ofthe other herein described indicators may be used as well. In certainembodiments, compounds will exhibit a 10- to 100-fold decrease in CNSactivity for a given behavior, e.g., will exhibit at least a 15-fold, orat least a 20-fold, or at least a 25-fold, or at least a 30-fold, or atleast a 40-fold, or at least a 50-fold, or at least a 60-fold, or atleast a 70-fold, or at least an 80-fold, or at least a 90-fold, or a100-fold or greater decrease in CNS activity for one of the indicativebehaviors observed. International Patent Application Publication No. WO2011/088140 provides a summary of reduction of CNS activity related to agiven behavior for the particular oligomeric-PEG opioid agonistcompounds investigated. As can be seen from the data presented therein,significant reductions in CNS-related behaviors were observed for eachof the oligomeric-PEG opioids.

As a reference, the illustrative PEG-opioid agonist compounds evaluatedin International Application Publication No. WO 2011/088140 demonstratestriking advantages in terms of significantly reduced CNS side effects,even when administered at a dose correlated with maximal analgesiceffect. CNS side effects that may accompany administration of opioidsinclude cognitive failure, organic hallucinations, respiratorydepression, sedation, myoclonus (involuntary twitching), and delirium,among others. When assessing one or more of the foregoing side-effects,the physician should ideally evaluate the patient to exclude otherunderlying etiologies. As such, the compositions and combinationsdescribed herein may be used to reduce one or more CNS side-effectsrelated to administration of an opioid analgesic by administering theopioid agonist compound in combination with an analgesic. In oneembodiment of the method, the amount of opioid agonist compoundadministered results in both an analgesic effect and a reduction of oneor more central nervous system side effects associated withadministration of the parent opioid agonist in a mammalian subject. Inone or more related embodiments, the method further comprises monitoringthe patient over the course of treatment for the existence and orabsence of one or more CNS-side effects associated with administrationof the opioid analgesic. In the event the existence of one or moreCNS-side effects is observed, the monitoring may further comprise anassessment of the degree of the CNS-side effect. The monitoring may thenfurther comprise a comparison of the degree or magnitude of the reducedCNS-side effect relative to the degree or magnitude of such CNS-sideeffect associated with the administration of the unmodified opioidagonist.

One advantage of administering the compositions and combinations of thepresent invention is that a reduction in speed of delivery of the opioidagonist to the brain is achieved, thus avoiding the rapid peakconcentrations associated with the parent opioid agonists and underlyingaddictive highs. Moreover, based on the covalent modification of theopioid agonist molecule, the compounds of the invention are not subjectto the risk of physical tampering that allows for the recovery and abuseof the rapid acting opioid agonists associated with certain alternativedelivery forms intended to provide, in vivo, a reduced BBB crossingrate. As such, the opioid agonist compounds of the invention possess lowaddictive, anti-abuse properties. The desired pharmacokinetic propertiesof the opioid agonist compounds may be modulated by selecting theoligomer molecular size, linkage, and position of covalent attachment tothe opioid agonist. One of ordinary skill in the art can determine theideal molecular size of the oligomer based upon the teachings herein.

As previously described, the present disclosure relates to compositionsand combinations comprising an opioid agonist compound (e.g. of theformula: OPIOID-X-POLY) and an analgesic compound. Analgesic compoundgenerally refers to and is meant to encompass certain drugs that areused to alleviate pain. Specific analgesics listed herein are meant tobe exemplary and not to limit the invention as such.

In certain embodiments, the analgesic compound is a non-steroidalanti-inflammatory drug (NSAID). NSAIDs are generally used for the reliefof symptomatic pain, such as muscoskeletal pain, inflammatory relief,and other diseases or conditions such as headache, fever, postoperativepain, etc. In certain embodiments, the analgesic is an antipyretic drug.In certain embodiments, the analgesic is chosen from acetylsalicylicacid, choline salicylate, celecoxib, diclofenac, diclofenac potassium,diclofenac sodium, diclofenac sodium/misoprostol, diflunisal, etodolac,fenoprofen calcium, flurbiprofen, ibuprofen, indomethacin, ketoprofen,magnesium salicylate, meclofenamate sodium, mefenamic acid, meloxicam,nabumetone, naproxen, naproxen sodium, oxaprozin, piroxicam, rofecoxib,salsalate, sodium salicylate, sulindac, tolmetin sodium, valdecoxib,choline magnesium trisalicylate, and ketorolac. In certain embodiments,the analgesic is chosen from ketorolac, ibuprofen, oxaprozin,indomethecin, etodolac, meloxicam, sulindac, diclofenac, flufenamicacid, difunisal, naproxen, flurbiprofen, ketoprofen, and fenoprofen. Incertain embodiments, the analgesic is selected from ketorolac,ibuprofen, oxaprozin, indomethecin, etodolac, sulindac, diclofenac,flufenamic acid, difunisal, naproxen, flurbiprofen, ketoprofen,fenoprofen, and acetaminophen. In certain embodiments the analgesiccompound is diclofenac.

In certain embodiments, the analgesic compound is not an opioidantagonist. In certain embodiments, the analgesic compound is not anopioid agonist.

As disclosed herein, the present compositions comprise an opioid agonistcompound (e.g. of the formula: OPIOID-X-POLY) and an analgesic compound.In certain embodiments, the analgesic compound is an analgesic compoundother than the parent opioid that is represented by OPIOID (or a residuethereof). In other words, for example, in certain embodiments, whenOPIOID is a codeine moiety bound to X-POLY, the analgesic is not codeine(or a residue thereof).

The compositions and combinations provided herein are useful in thetreatment of pain. Generally, treatment comprises administering ananalgesically effective amount of an opioid agonist compound (e.g. acompound having a formula OPIOID-X-POLY) and an analgesic as disclosedherein above, either as part of a composition or as a combination.Generally, such treatment is for the management of pain (e.g., acute orchronic pain). The compositions and combinations provided herein may,for example, be used to treat nociceptive pain. The compositions andcombinations provided herein may, for example, be used to treat visceralpain, musculo-skeletal pain, nerve pain, and/or sympathetic pain.Representative studies demonstrating the ability of the opioid agonistcompounds to reduce or prevent pain are provided in at least U.S. PatentApplication Publication No. 2010/0048602, International PatentApplication Publication No. WO 2008/112288, International PatentApplication Publication No. WO 2010/033195, U.S. Patent ApplicationPublication No. 2011/0237614, International Patent ApplicationPublication No. WO 2011/011543, U.S. Patent Application Publication No.2012/0184581, International Patent Application Publication No. WO2011/088140, and U.S. patent application Ser. No. 13/521,556.Administration of the compositions and combinations provided herein may,for example, be used in the treatment of chronic pain ranging frommoderate to severe, including neuropathic pain. Neuropathic pain is paindue to nerve injury, neurologic disease, or the involvement of nervesdue to other disease processes. The compositions and combinationsdescribed herein may be used in the treatment of pain associated withany of a number of conditions such as cancer, fibromyalgia, lower backpain, neck pain, sciatica, osteoarthritis, and the like. Thecompositions and combinations may also be used for relievingbreakthrough pain.

All articles, books, patents, patent publications and other publicationsreferenced herein are hereby incorporated by reference in theirentireties.

It is to be understood that while the invention has been described inconjunction with certain and specific embodiments, the foregoingdescription as well as the examples that follow are intended toillustrate and not limit the scope of the invention. Other aspects,advantages and modifications within the scope of the invention will beapparent to those skilled in the art to which the invention pertains.

EXAMPLES

All chemical reagents referred to in the appended examples arecommercially available unless otherwise indicated. The preparation ofPEG-mers is described in, for example, U.S. Patent ApplicationPublication No. 2005/0136031. Additionally, opioid agonist compound maybe prepared as disclosed in U.S. Patent Application Publication No.2010/0048602. Examples 1-3 are a reproduction of Examples 15-17 fromU.S. Patent Application Publication No. 2010/0048602. Examples 4-6 are areproduction of Examples 11-13 from U.S. Patent Application PublicationNo. 2010/0048602.

Example 1 Preparation of mPEG_(n)-O-Morphine Compounds

The following describes the preparation of free base using commerciallyavailable morphine sulfate hydrate (generally procedure).

Morphine sulfate USP from Spectrum (510 mg) was dissolved in water (70ml). The solution was then basified to pH 10 using aqueous K₂CO₃ to givea white suspension. To the white suspension DCM (dichloromethane, 50 ml)was added, but failed to dissolve the solid. The mixture was made acidicwith 1M HCl to result in clear biphasic solution. The organic phase wassplit off and the aqueous phase was carefully brought to pH 9.30(monitored by a pH meter) using the same solution of K₂CO₃ as above. Awhite suspension resulted again. The heterogeneous mixture was extractedwith DCM (5×25 ml) and an insoluble white solid contaminated both theorganic and aqueous layers. The organic layer was dried with MgSO₄,filtered and rotary evaporated to yield 160 mg of morphine free base(56% recovery). No additional product was recovered from the filter cakeusing MeOH, but another 100 mg was recovered from the aqueous phase by2×50 ml extraction with EtOAc to give a combined yield of 260 mg (68%).

MEM Protection of Morphine Free Base

The general approach for protecting the free base of morphine with theprotecting group ⊖-methoxyethoxymethyl ether (“MEM”) is schematicallyshown below.

Free base morphine (160 mg, 0.56 mmol) was dissolved in 20 ml ofAcetone/Toluene (2/1 mixture). To the resulting solution was added K₂CO₃(209 mg, 1.51 mmol, 2.7 eq) followed by MEMCl (96 μl, 0.84 mmol, 1.5 eq)and the resulting heterogeneous mixture was stirred overnight at roomtemperature. After five hours at room temperature, the reaction wasdeemed comlete by LC-MS. Morphine free base retention time understandard six minute gradient run conditions (std 6 min, Onyx MonolythC18 column, 50×4.6 mm; 0 to 100% Acetonitrile 0.1% TFA in Water 0.1%TFA, 1.5 ml/min; detection: UV254, ELSD, MS; retention times are quotedfor UV254 detector, ELSD has about 0.09 min delay and MS has about 0.04min delay relative to UV) was 1.09 min; retention time for product 1.54min (std 6 min), major impurity 1.79 min. The reaction mixture wasevaporated to dryness, dissolved in water, extracted with EtOAc (3×,combined organic layer washed with brine, dried over MgSO₄, filtered androtary evaporated) to give 160 mg (77%) of the desired product as acolorless oil. Product purity was estimated to be about 80% by UV254.

Direct MEM Protection of Morphine Sulfate (General Procedure)

The general approach for protecting morphine sulfate with the protectinggroup β-methoxyethoxymethyl ether (“MEM”) is schematically shown below.Although not explicitly shown in the scheme below, morphine is actuallymorphine sulfate hydrate, morphine.0.5 H₂SO_(4.)2.5 H₂O.

To a suspension of 103 mg of morphine sulfate hydrate (0.26 mmol) in 10ml of 2:1 acetone:toluene solvent mixture was added 135 mg (1 mmol, 3.7eq) of K₂CO₃ and the suspension stirred at room temperature for 25minutes. To the resulting suspension was added 60 μl (0.52 mmol) ofMEMCl and the mixture allowed to react at room temperature. It wassampled after one hour (38% nominal conversion, additional peaks at 1.69min and 2.28 min), three hours (40% nominal conversion, additional peakat 1.72 min (M+1=493.2)), four and one-half hours (56% nominalconversion, additional peak at 1.73 min), and twenty-three hours (>99%nominal conversion, additional peak at 1.79 min—about 23% of the productpeak by height in UV₂₅₄); thereafter, the reaction was quenched withMeOH, evaporated, extracted with EtOAc to give 160 mg of clear oil.

The same reaction was repeated starting with 2 g (5.3 mmol) of morphinesulfate hydrate, 2.2 g (16 mmol, 3 eq) of K₂CO₃, 1.2 ml (10.5 mmol, 2eq) of MEMCl in 100 ml of solvent mixture. Sampling occurred after twohours (61% nominal conversion, extra peak at 1.72 min (M+1=492.8)),after one day (80% nominal conversion, extra peak at 1.73 min), afterthree days (85% nominal conversion, only small impurities, 12 mingradient run), and after six days (91% conversion); thereafter, thereaction was quenched, evaporated, extracted with EtOAc, purified oncombi-flash using a 40 g column, DCM:MeOH 0 to 30% mobile phase. Threpeaks (instead of two) were identified, wherein the middle peak wascollected, 1.15 g (58% yield) of light yellow oil, UV₂₅₄ purity about87%.

Conjugation of MEM-Protected Morphine to Provide a MEM-ProtectedMorphine Compound

The general approach for conjugating MEM-protected morphine with awater-soluble oligomer to provide a MEM-protected morphine PEG-oligomercompound is schematically shown below.

To a solution of toluene/DMF (2:1 mixture, 10 volumes total) was chargedMEM-morphine free base followed by NaH (4-6 eq) and then PEG_(n)OMs(1.2-1.4 eq.), previously prepared. The reaction mixture was heated to55-75° C. and was stirred until reaction completion was confirmed byLC-MS analysis (12-40 hours depending on PEG chain length). The reactionmixture was quenched with methanol (5 volumes) and the reaction mixturewas evaporated to dryness in vacuo. The residue was redissolved inmethanol (3 volumes) and was chromatographed using a Combiflash system(0-40% MeOH/DCM). The fractions containing large amounts of product werecollected, combined and evaporated to dryness. This material was thenpurified by RP-HPLC to give the products as yellow to orange oils.

Deprotection of MEM-Protected Morphine Compound to Provide a MorphineCompound

The general approach for deprotecting a MEM-protected morphine compoundto provide a morphine compound is schematically shown below.

To a solution of MEM-protected morphine compound TFA salt suspended inDCM (8 volumes) was charged 6 volumes of 2M HCl in diethyl ether. Thereaction mixture was allowed to stir at room temperature for two hoursand was then evaporated to dryness under reduced pressure. The oilyresidue was dissolved in MeOH (8 volumes), filtered through glass wooland then evaporated under reduced pressure to give a thick orange toyellow oil in quantitative yield. Compounds made by this method include:α-6-mPEG₃-O-morphine (Compound A, n=3) 217 mg of HCl salt 97% pure (95%by UV254; 98% by ELSD); α-6-mPEG₄-O-morphine (Compound A, n=4) 275 mg ofHCl salt 98% pure (97% by UV254; 98% by ELSD); α-6-mPEG₅-O-morphine(Compound A, n=5) 177 mg of HCl salt 95% pure (93% by UV254; 98% byELSD); α-6-mPEG₆-O-morphine (Compound A, n=6) 310 mg of HCl salt 98%pure (98% by UV254; 99% by ELSD); α-6-mPEG₇-O-morphine (Compound A, n=7)541 mg of HCl salt 96% pure (93% by UV254; 99% by ELSD); andα-6-mPEG-O₉-morphine (Compound A, n=9) 466 mg of HCl salt 98% pure (97%by UV254; 99% by ELSD). Additionally, morphine compounds having a singlePEG monomer attached, α-6-mPEG₁-O-morphine (Compound A, n=1), 124 mg ofHCl salt, 97% pure (95% pure by UV₂₅₄; 98% by ELSD); as well asα-6-mPEG₂-O-morphine (Compound A, n=2), 485 mg of HCl salt, 97% pure(95% pure by UV₂₅₄; 98% by ELSD) were similarly prepared.

Example 2 Preparation of mPEG_(n)-O-Codeine Compounds

The general approach for conjugating codeine with an activated sulfonateester of a water-soluble oligomer (using mPEG₃OMs as a representativeoligomer) to provide a codeine compound is schematically shown below.

Codeine (30 mg, 0.1 mmol) was dissolved in toluene/DMF (75:1) solventmixture followed by addition of HO—CH₂CH₂OCH₂CH₂OCH₂CH₂OMs (44 ml, 2eq)and NaH (60% suspension in mineral oil, 24 mg, 6 eq). The resultinghomogeneous yellow solution was heated to 45° C. After one hour, thereaction showed 11% conversion (extra peak at 2.71 min, 12 min run),after eighteen hours, the reaction showed 7% conversion (extra peak at3.30 min, 12 min run), and after 24 hours, the reaction showed 24%conversion (multitude of extra peaks, two tallest ones are 1.11 min and2.79 min). At this point, an additional 16 mg of NaH was added andheating continued for six hours, after which, an additional 16 mg of NaHwas added followed by continued heating over sixty-six hours.Thereafter, no starting material remained, and analysis revealed manyextra peaks, the two tallest ones corresponding to 2.79 min and 3 min(product peak is the second tallest among at least 7 peaks).

This synthesis was repeated using 10× scale wherein 30 ml of solventmixture was used. After eighteen hours, analysis revealed 71% nominalconversion with additional peaks in the UV (one tall peak at 3.17 minand many small ones; wherein the desired peak corresponded to 3.43 minin UV). Thereafter, 80 mg (2 mmol) of NaH was added followed bycontinued heating. After three hours, analysis revealed 85% nominalconversion (several extra peaks, main 3.17 min). Reaction mixture wasdiluted with water, extracted with EtOAc (3×, combined organic layerwashed with brine, dried over MgSO₄, filtered and rotary evaporated) togive yellow oil (no sm in LC-MS, 90% pure by ELSD, 50% pure by UV—majorimpurity at 3.2 min). The crude product was dissolved in DCM, applied toa small cartridge filled with 230-400 mesh SiO₂, dried, eluted on aCombi-flash via a 4 g pre-packed column cartridge with solvent A=DCM andsolvent B=MeOH, gradient 0 to 30% of B. Analysis revealed two peaks ofpoor symmetry: a small leading peak and a larger peak with a tail. LC-MSwas used to analyze fractions, wherein none were identified ascontaining pure product. Combined fractions that contained any product(t022-30) yielded, following solvent evaporation, 150 mg (34% yield) ofimpure product (LC-MS purity at 3.35 min by UV254, wherein about 25%represented the main impurities 3.11 min, 3.92 min, 4.32 min, 5.61 minof a 12 min run). A second purification by HPLC (solvent A=water, 0.1%TFA; solvent B=acetonitrile, 0.1% TFA) employing a gradientcorresponding to 15-60% B, 70 min, 10 ml/min) resulted in poorseparation from adjacent peaks. Only two fractions were clean enough andgave 21 mg of TFA salt (>95% pure, 4.7% yield). Three additionalfractions both before and after the desired product-containing fractions(for a total of six additional fractions were combined to give 70 mg ofabout 50% pure product as TFA salts.

Using this same approach, other compounds differing by the number ofethylene oxide units (n=4, 5, 6, 7, and 9) were made using these NaHconditions outlined above.

Conversion of Codeine-Oligomer Compound TFA Salts to Codeine-OligomerCompound HCl salts.

The general approach for converting codeine-oligomer TFA salts tocodeine-oligomer HCl salts is schematically shown below.

To a solution of codeine-oligomer compound TFA salt suspended in DCM (8volumes) was charged 6 volumes of 2M HCl in diethyl ether. The reactionmixture was allowed to stir at room temperature for two hours and wasthen evaporated to dryness under reduced pressure. The oily residue wasdissolved in MeOH (8 volumes), filtered through glass wool and thenevaporated under reduced pressure to give a thick orange to yellow oilin quantitative yield. Following this general procedure, the followingcompounds were synthesized: α-6-mPEG₃-O-codeine (Compound B, n=3) 235 mgof HCl salt, 98% pure; α-6-mPEG₄-O-codeine (Compound B, n=4) 524 mg ofHCl salt, 98% pure; α-6-mPEG₅-O-codeine (Compound B, n=5) 185 mg of HClsalt, 98% pure+119 mg of HCl salt 97% pure, α-6-mPEG₆-O-codeine(Compound B, n=6) 214 mg of HCl salt, 97% pure; α-6-mPEG₇-O-codeine(Compound B, n=7) 182 mg of HCl salt, 98% pure; α-6-mPEG₉-O-codeine(Compound B, n=9) 221 mg of HCl salt, 97% pure; α-6-mPEG₁-O-codeine(Compound B, n=1) 63 mg of HCl salt, 90% pure; and α-6-mPEG₂-O-codeine(Compound B, n=2) 178 mg of HCl salt, 90% pure.

Example 3 Preparation of mPEG_(n)-O-Hydroxycodone Compounds

The general approach for conjugating hydroxycodone with an activatedsulfonate ester of a water-soluble oligomer (using “mPEG_(n)OMs” as arepresentative oligomer) to provide a hydroxycodone compound isschematically shown below.

Reduction of Oxycodone to α-6-hydroxycodone:

To a solution of oxycodone free base in dry THF under nitrogen cooled at−20° C., was added a 1.0 M THF solution of potassiumtri-sec-butylborohydride over 15 minutes. The solution was stirred at−20 ° C. under nitrogen for 1.5 hours and then water (10 mL) was addedslowly. The reaction mixture was stirred another 10 minutes at −20 ° C.and then allowed to warm to room temperature. All solvents were removedunder reduced pressure and CH₂Cl₂ was added to the remaining residue.The CH₂Cl₂ phase was extracted with a 0.1 N HCl/NaCl water solution andthe combined 0.1 N HCl solution extracts were washed with CH₂Cl₂, thenNa₂CO₃ was added to adjust the pH=8. The solution was extracted withCH₂Cl₂. The CH₂Cl₂ extracts were dried over anhydrous Na₂SO₄. Afterremoving the solvent under reduced pressure, the desiredα-6-HO-3-hydroxycodone was obtained.

Conjugation of mPEG_(n)OMs to α-6-hydroxycodone:

To a solution of Toluene/DMF (2:1 mixture, 10 volumes total) was chargedhydroxycodone (prepared as set forth in the preceding paragraph)followed by NaH (4 eq) and then mPEG_(n)OMs (1.3 e.). The reactionmixture was heated to 60-80° C. and was stirred until reactioncompletion was confirmed by LC-MS analysis (12-40 hours depending on PEGchain length). The reaction mixture was quenched with methanol (5volumes) and the reaction mixture was evaporated to dryness in vacuo.The residue was re-dissolved in methanol (3 volumes) and waschromatographed using Combiflash (0-40% MeOH/DCM). The fractionscontaining large amounts of product were collected, combined andevaporated to dryness. This material was then purified by RP-HPLC toprovide the final products as yellow to orange oils.

Conversion of Hydroxycodone Compound TFA Salts to Hydroxycodone CompoundHCl Salts

To a solution of hydroxycodone compound TFA salt suspended in DCM (8volumes) was charged 6 volumes of 2M HCl in diethyl ether. The reactionmixture was allowed to stir at room temperature for two hours and wasthen evaporated to dryness under reduced pressure. The oily residue wasdissolved in MeOH (8 volumes), filtered through glass wool and thenevaporated under reduced pressure to give a thick orange to yellow oilin quantitative yield. Following this general procedure, the followingcompounds were synthesized: α-6-mPEG₃-O-oxycodone (akaα-6-mPEG₃-O-hydroxycodone) (Compound C, n=3) 242 mg of HCl salt, 96%pure; α-6-mPEG₄-O-oxycodone (aka α-6-mPEG₄-O-hydroxycodone) (Compound C,n=4) 776 mg of HCl salt, 94% pure; α-6-mPEG₅-O-oxycodone (akaα-6-mPEG₅-O-hydroxycodone) (Compound C, n=5) 172 mg of HCl salt, 93%pure; α-6-mPEG₆-O-oxycodone (aka α-6-mPEG₆-O-hydroxycodone) (Compound C,n=6) 557 mg of HCl salt, 98% pure; α-6-mPEG₇-O-oxycodone (akaα-6-mPEG₇-O-hydroxycodone) (Compound C, n=7) 695 mg of HCl salt, 94%pure; and α-6-mPEG₉-O-oxycodone (aka α-6-mPEG₉-O-hydroxycodone)(Compound C, n=9) 435 mg of HCl salt 95% pure. The following compounds,α-6-mPEG₁-O-oxycodone (aka α-6-mPEG₁-O-hydroxycodone) (Compound C, n=1)431 mg of HCl salt 99% pure; and α-6-mPEG₂-O-oxycodone (akaα-6-mPEG₂-O-hydroxycodone) (Compound C, n=2) 454 mg HCl salt, 98% pure,were similarly prepared.

Example 4 Preparation of Oligomer-Fentanyl Compounds

mPEG_(n)-O-fentanyl compounds can be prepared following the approachesschematically shown below. Conventional organic synthetic techniques areused in carrying out the synthetic approaches.

An exemplary approach for preparing the following structures, where thePEG oligomer is positioned, i.e., covalently attached, at theN-(1-(2-phenylethyl)piperidin-4-yl) phenyl group:

[wherein mPEG_(n) is —(CH₂CH₂O)_(n)—CH₃ and n is an integer from 1 to9], is provided below.

In the above approach, the starting material is a(haloethyl)hydroxybenzene, where the hydroxy group forms the point ofattachment for the PEG oligomer. The (haloethyl)hydroxybenzene, i.e.,(bromoethyl)hydroxybenzene, is reacted with a mesylated or halogenatedactivated mPEG oligomer, thereby forming the desired PEG-oligomermodified (haloethyl)benzene intermediate. This intermediate is thenreacted with piperidin-4-one in the presence of a phase transfercatalyst; the bromo group reacts at the piperidine-4-one nitrogen toform a next intermediate, 1-(mPEG_(olig)-phenylethyl)piperidine-4-one.The ketone functionality is then reduced in the presence of a reducingagent such as sodium borohydride, and converted to an amino group, i.e.,N-phenyl-piperidin-4-amine, by reaction with aniline. Finally, thesecondary amino group is converted to a tertiary amine by reaction withpropionyl chloride to form the desired product as indicated in thescheme above.

The subject mPEG_(n)-O-fentanyl compounds having the PEG oligomerpositioned at the N-(1-(2-phenylethyl)piperidin-4-yl) phenyl group weresynthesized using a reaction scheme that was slightly modified fromScheme 4-A above as illustrated in Scheme 4-B below:

The above approach employs tosyl (p-toluenesulfonate) leaving groups atvarious steps in the synthesis. The desired PEG-oligomer compounds (n=1to 9) were assembled by reacting di-tosylated 3-(2-hydroxyethyl)phenolwith N-phenyl-N-(piperidin-4-yl)propionamide to formN-(1-(3-hydroxyphenylethyl)piperidin-4-yl)-N-phenylpropionamide, intosylated form, followed by removal of the tosyl group. The PEG-oligomergroup was then introduced into the molecules at the phenyl hydroxylposition by reaction ofN-(1-(3-hydroxyphenylethyl)piperidin-4-yl)-N-phenylpropionamide with amolar excess of mPEG_(olig)-tosylate to form the desiredmPEG_(n)-O-fentanyl compounds. Ratios of reactants and reactionconditions generally employed are provided in the reaction scheme above.

An exemplary approach for providing the following structures, where thePEG oligomer is positioned, i.e., covalently attached, at the N-phenylgroup, is set forth below:

The above exemplary approach for forming an mPEG_(n)-O-fentanyl compoundhaving the PEG oligomer positioned at the N-phenyl ring starts with,e.g., 2-bromoethylbenzene, as the starting material. The2-bromoethylbenzene is reacted with piperidin-4-one in the presence of aphase transfer catalyst to thereby form the resulting1-phenethylpiperidin-4-one. The 1-phenethylpiperidin-4-one is coupled tomPEG_(olig)-substituted aniline, which is prepared by taking N-protectedhydroxyaniline and reacting it with activated mPEG oligomer, such asbromomethoxyPEG_(olig) or mPEG_(oligo) mesylate, followed by removal ofthe protecting group (see step (b) above). As indicated in reaction step(c) above, 1-phenethylpiperidin-4-one is reacted withmPEG_(olig)-substituted aniline in the presence of a reducing agent toconvert the keto group into an amine to form the intermediate,1-phenylethylpiperidin-4-ylamino-mPEG_(olig)obenzene. Finally, thesecondary amino group is converted to a tertiary amine by reaction withpropionyl chloride to form the desired product as indicated in thescheme above.

The subject mPEG_(n)-O′-fentanyl compounds having the PEG oligomerpositioned at the N-phenyl group were synthesized using a reactionscheme that was slightly modified from Scheme 4-C above as illustratedin Scheme 4-D below:

As indicated in Scheme 4-D above, the desired mPEG_(n)-O-fentanylcompounds were prepared by first reacting 1-phenethylpiperidin-4-onewith 3-aminophenol under reducing conditions to thereby convert the ketofunctionality into an amine, i.e., by reaction with the amino group of3-aminophenol. The product, 3-(1-phenethylpiperidin-4-ylamino)phenol,was then reacted with propionic anhydride in the presence of base (e.g.,triethyl amine) and dimethylaminopyridine (DMAP) under conditionseffective to formN-(3-hydroxyphenyl)-N-(1-phenethylpiperidin-4-yl)propionamide. Finally,introduction of the oligomeric PEG functionality was carried out byreacting the precursor,N-(3-hydroxyphenyl)-N-(1-phenethylpiperidin-4-yl)propionamide, with amolar excess of mPEG_(oligo)tosylate under coupling conditions effectiveto form the desired compounds. Ratios of reactants and reactionconditions generally employed are provided in the reaction schemesabove.

Example 4A Preparation of m-mPEG_(n)-O-Fentanyl Compounds

Synthesis of m-mPEG₁-O-Fentanyl Compound (n=1):

Using an approach set forth in Example 4 and as described schematicallyin Scheme 4-B, the above compound was prepared.

Synthesis of m-mPEG₂-O-Fentanyl Compound (n=2):

Using an approach set forth in Example 4 and as described schematicallyin Scheme 4-B, the above compound was prepared.

Synthesis of m-mPEG₃-O-Fentanyl Compound (n=3):

Using an approach set forth in Example 4 and as described schematicallyin Scheme 4-B, the above compound was prepared.

Synthesis of m-mPEG₄-O-Fentanyl Compound (n=4):

Using an approach set forth in Example 4 and as described schematicallyin Scheme 4-B, the above compound was prepared.

Synthesis of m-mPEG₅-O-Fentanyl Compound (n=5):

Using an approach set forth in Example 4 and as described schematicallyin Scheme 4-B, the above compound was prepared.

Synthesis of m-mPEG₆-O-Fentanyl Compound (n=6):

Using an approach set forth in Example 4 and as described schematicallyin Scheme 4-B, the above compound was prepared.

Synthesis of m-mPEG₇-O-Fentanyl Compound (n=7):

Using an approach set forth in Example 4 and as described schematicallyin Scheme 4-B, the above compound was prepared.

Synthesis of m-mPEG₇-O-Fentanyl Compound (n=7):

Using a similar approach set forth in Example 4 and as describedschematically in Scheme 4-B, the above compound was prepared.

Synthesis of m-mPEG₈-O-Fentanyl Compound (n=8)

Using an approach set forth in Example 4 and as described schematicallyin Scheme 4-B, the above compound was prepared.

Synthesis of m-mPEG₉-O-Fentanyl Compound (n=9):

Using an approach set forth in Example 4 and as described schematicallyin Scheme 4-B, the above compound was prepared.

Each of the above mPEG₁₋₉-O-fentanyl compounds was characterized by ¹HNMR (200 MHz Bruker) and by LC/MS.

Example 5 Preparation of m-mPEG₁-O′-Fentanyl Compounds

Synthesis of m-mPEG₁-O′-Fentanyl Compound (n=1):

Using an approach set forth in Example 4 and as described schematicallyin Scheme 4-D, the above compound was prepared. In this series, theoligomeric mPEG was covalently attached at the meta-position of theN-phenyl group.

Synthesis of m-mPEG₂-O′-Fentanyl Compound (n=2):

The above compound was prepared using the approach set forth in Example4 and as described schematically in Scheme 4-D.

Synthesis of m-mPEG₃-O′-Fentanyl Compound (n=3):

The above compound was prepared using the approach set forth in Example4 and as described schematically in Scheme 4-D.

Synthesis of m-mPEG₄-O′-Fentanyl Compound (n=4):

The above compound was prepared using the approach set forth in Example4 and as described schematically in Scheme 4-D.

Synthesis of m-mPEG₅-O′-Fentanyl Compound (n=5):

The above compound was prepared using the approach set forth in Example4 and as described schematically in Scheme 4-D.

Synthesis of m-mPEG₆-O′-Fentanyl Compound (n=6):

The above compound was prepared using the approach set forth in Example4 and as described schematically in Scheme 4-D.

Synthesis of m-mPEG₇-O′-Fentanyl Compound (n=7):

The above compound was prepared using the approach set forth in Example4 and as described schematically in Scheme 4-D.

Synthesis of m-mPEG₈-O′-Fentanyl Compound (n=8):

The above compound was prepared using the approach set forth in Example4 and as described schematically in Scheme 4-D.

Synthesis of m-mPEG₈-O′-Fentanyl Compound (n=8)

The above compound was prepared using the approach set forth in Example4 and as described schematically in Scheme 4-D.

Synthesis of m-mPEG₉-O′-Fentanyl Compound (n=9):

The above compound was prepared using the approach set forth in Example11 and as described schematically in Scheme 4-D.

Each of the above mPEG₁₋₉-O′-fentanyl compounds were characterized by ¹HNMR (200 MHz Bruker) and by LC/MS.

Example 6 Preparation of para-mPEG_(n)-O′-Fentanyl Compounds

Synthesis of p-mPEG₁-O′-Fentanyl Compound (n=1):

The above compound can be prepared using an approach set forth inExample 4. In this series, the oligomeric mPEG is covalently attached atthe para-position of the N-phenyl group.

Synthesis of p-mPEG₄-O′-Fentanyl Compound (n=4)

The para-substituted compound was prepared according to the reactionscheme shown below:

The desired pPEG₄-O-fentanyl compound was prepared by first reacting1-phenethylpiperidin-4-one with 4-aminophenol under reducing conditions(e.g., in the presence of a reducing agent such as NaBH(OAc)₃) tothereby convert the keto functionality into an amine, i.e., by reactionwith the amino group of 4-aminophenol. The product,4-(1-phenethylpiperidin-4-ylamino)phenol, was then reacted withpropionic anhydride in the presence of base (e.g., triethyl amine) anddimethylaminopyridine (DMAP) under conditions effective to formN-(4-hydroxyphenyl)-N-(1-phenethylpiperidin-4-yl)propionamide. Finally,introduction of the oligomeric PEG functionality was carried out byreacting the precursor,N-(4-hydroxyphenyl)-N-(1-phenethylpiperidin-4-yl)propionamide, with amPEG₄tosylate under coupling conditions effective to form the desiredcompound. Ratios of reactants and reaction conditions generally employedare provided in the reaction scheme above.

Additional pPEG_(oligo)-O-fentanyl compounds may be similarly prepared.

Example 7 In Vivo Analgesis Assay: Acetic Acid Writhing in Mice

The analgesic potency of certain oligomeric PEG-opioid compounds,mPEG_(n)-O-hydroxycodone (e.g. α-6-mPEG_(n)-O-hydroxycodone, See Example3), in combination with diclofenac were determined using an acetic acidwrithing assay in mice.

Mice were given a single dose of control solution or two separate oraldoses (larger volume immediately after administration of a smallervolume) of a PEG-opioid agonist compound (α-6-mPEG_(n)-O-hydroxycodone(n=4, 5, 6)) and diclofenac 30 minutes prior to intraperitonealadministration of 0.5% acetic acid (0.1 mL/10 g bodyweight). Acetic acidinduces “writhing” which includes: contractions of the abdomen, twistingand turning of the trunk, arching of the back and the extension of thehindlimbs. After the injection the animals were placed in an observationbeaker and their behavior was observed. Contractions were counted infour, five minute segments, between 0 and 20 minutes after the aceticacid injection. The animals were used once and euthanized immediatelyfollowing the completion of the study. Each compound was tested at doserange of 1-100 mg/kg.

Table 1 provides a summary the acetic acid writhing mean total number ofwrithes for the tested compounds in combination with Diclofenac (3mg/kg).

TABLE 1 Mean Number of writhes Dose α-6-mPEG₄-O- α-6-mPEG₅-O-α-6-mPEG₆-O- (mg/kg) hydroxycodone hydroxycodone hydroxycodone 5 13 7.26.2 10 4.8 1.4 4

FIG. 1 shows the dose response graphs from the acetic acid writing assayfor α-6-mPEG_(n)-O-hydroxycodone (n=5) and diclofenac, administeredseparately, respectively. FIG. 2 shows the results of the acetic acidwrithing assay for a combination of mPEG_(n)-hydroxycodone(α-6-mPEG_(n)-O-hydroxycodone) (n=5) and diclofenac (3 mg/kg). As seenin FIG. 2, the combination of mPEG_(n)-hydroxycodone(α-6-mPEG_(n)-O-hydroxycodone) (n=5) and diclofenac results in ameasured reduction of writhings that is greater than the number ofwrithings when each compound is individually administered.

Prophetic Example 8 In-Vivo Analgesic Assay: Hot Plate Latency Assay

The hot plate latency assay may be used as a measure of in vivobioactivity of the compositions and combinations disclosed herein. Thisexperiment uses a standard hotplate withdrawal assay in which latency ofwithdrawal from a heat stimulus is measured following administration ofa test compound. Compounds are administered to the animal and 30 minuteslater, a thermal stimulus is provided to the hindpaw. Latency forhindpaw withdrawal in the presence of morphine is used as the measure offull analgesia, while latency in the presence of saline is used as anegative control for no analgesia. The agonist effect of the testcompound is evaluated by measuring time to withdrawal compared with anegative control (saline).

Prophetic Example 9 Evaluation of Opioid Agonist Compounds and NSAIDS ina Rat Model of Inflammation

The effects of NSAIDS and PEG-opioid agonist compounds alone and ascombination are evaluated in a rat model of inflammatory pain. Aninjection of 50% Complete Freund's adjuvant (CFA) is injectedintra-plantar into the hind paw of rats to induce inflammation. Two dayslater, test compounds are administered orally to rats within a range ofspecified doses. CFA evoked mechanical hyperalgesia is measured atbaseline and at various times following treatment with test compoundsusing a paw pressure test (Randall Sellito). CFA causes significantdecrease in the paw withdrawal thresholds (baseline) and doses of testcompounds or combinations that produce a significant increase in the pawwithdrawal threshold from baseline are considered to be efficacious inthis model.

1. A composition comprising an opioid agonist compound and at least oneanalgesic compound. 2.-31. (canceled)
 32. A method of treating pain in apatient, comprising: co-administering (i) an opioid agonist compoundhaving the formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is hydrogenor methyl; R² is hydrogen or hydroxyl; R³ is hydrogen, methyl, orcyclobutylmethyl; R⁴ is hydrogen; “---” represents an optional doublebond; Y¹ is O; X is a physiologically stable linker; n is an integerfrom 1 to 10; and Y is lower alkyl; and (ii) a non-steroidalanti-inflammatory drug (NSAID) to a patient in need thereof. 33.-36.(canceled)
 37. The method of claim 32, wherein the opioid agonistcompound is selected from the formulae:

wherein n is an integer selected from 1 to 10; or a pharmaceuticallyacceptable salt thereof.
 38. The method of claim 32, wherein the opioidagonist compound has the formula:

wherein n is an integer selected from 2 to 10; or a pharmaceuticallyacceptable salt thereof.
 39. (canceled)
 40. The method of claim 32,wherein n is
 2. 41. The method of claim 32, wherein n is
 3. 42. Themethod of claim 32, wherein n is
 4. 43. The method of claim 32, whereinn is
 5. 44. The method of claim 32, wherein n is
 6. 45. The method ofclaim 32, wherein n is
 7. 46. The method of claim 32, wherein n is 8.47. The method of claim 32, wherein n is
 9. 48. The method of claim 32,wherein n is
 10. 49.-57. (canceled)
 58. The method of claim 32, whereinthe analgesic compound is selected from ketorolac, ibuprofen, oxaprozin,indomethecin, etodolac, meloxicam, sulindac, diclofenac, flufenamicacid, difunisal, naproxen, flurbiprofen, ketoprofen, fenoprofen, andacetaminophen.
 59. The method of claim 32, wherein a singlenon-steroidal anti-inflammatory drug (NSAID) is co-administered. 60.(canceled)
 62. The method of claim 32, wherein each of the opioidagonist and the non-steroidal anti-inflammatory drug (NSAID) isco-administered orally.
 63. The method of claim 32, wherein theco-administration is selected from five times a day, four times a day,three times a day, twice daily, once daily, three times weekly, twiceweekly, once weekly, twice monthly, and once monthly.